Sealing protein 18.2 antibody as well as preparation method and application thereof

Abstract

Provided herein are antibodies and compositions against sealin 18.2 and uses thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Patent Application Serial No. 63 / 347,647, filed on June 1, 2022, entitled “CLAUDIN 18.2 ANTIBODIES, METHODS OF MAKING THE SAME, AND USES THEREOF,” which is incorporated herein by reference in its entirety.

[0003] Cross-references to electronically submitted sequence listings

[0004] This application contains a sequence listing, which has been submitted electronically as an XML file and is hereby incorporated by reference in its entirety. The XML copy was created on June 1, 2023, is named "ITL-020WO Sequence Listing.XML", and is 32,768 bytes in size. Background Art

[0005] Gastric tumors are often diagnosed and treated at an advanced tumor stage with a poor prognosis. Recent studies have identified isoform 2 of the tight junction protein claudin-18 ("claudin 18.2") as a promising target in gastric tumor therapy. Claudin 18.2 is expressed in gastric tumors but not in normal adult tissues except the gastric mucosa. Therefore, the relatively specific expression of claudin 18.2 on gastric tumors makes claudin 18.2 an attractive target. Due to the high similarity between claudin 18.2 and claudin 18.1, it is difficult to specifically target claudin 18.2. In addition, it is a structurally complex antigen and it is difficult to produce antibodies against the target. Therefore, there is a need in the art for antibodies against claudin 18.2 that can be used for different treatments. The embodiments provided herein meet these needs and other needs. Summary of the invention

[0006] In some embodiments, a recombinant antibody or an antigen binding fragment thereof that binds to a claudin 18.2 protein is provided. In some embodiments, the recombinant antibody or an antigen binding fragment thereof binds to a claudin 18.2 protein in its native conformation. In some embodiments, the antibody or an antigen binding fragment thereof specifically binds to claudin 18.2. In some embodiments, the antibody or an antigen binding fragment thereof does not specifically bind to claudin 18.1.

[0007] In some embodiments, the antibody or its antigen binding fragment binds to human claudin 18.2 protein. In some embodiments, the antibody or its antigen binding fragment that binds to claudin 18.2 protein is a humanized antibody. In some embodiments, the antibody or its antigen binding fragment that binds to claudin 18.2 protein is a chicken antibody. In some embodiments, the antibody or its antigenic fragment is generated by inducing an immune response against claudin 18.2 in chickens.

[0008] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein is a monoclonal antibody. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein is a scFv antibody.

[0009] In some embodiments, the antibody or antigen-binding fragment comprises: a light chain variable (V L ) region, the light chain variable region includes a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2) and a light chain CDR3 (LCDR3), wherein the LCDR1 has an amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23; the LCDR2 has an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24; and the LCDR3 has an amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof includes V L Area, the V L The region comprises LCDR1, LCDR2 and LCDR3, wherein the LCDR1 has an amino acid sequence of SEQ ID NO: 17; the LCDR2 has an amino acid sequence of SEQ ID NO: 18; and the LCDR3 has an amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof comprises V L Area, the V L The region includes LCDR1, LCDR2 and LCDR3, wherein the antibody or antigen-binding fragment thereof, wherein the LCDR1 has the amino acid sequence of SEQ ID NO:23; the LCDR2 has the amino acid sequence of SEQ ID NO:24; and the LCDR3 has the amino acid sequence of SEQ ID NO:19.

[0010] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises a light chain variable (V L) region, wherein the light chain variable region has an amino acid sequence that is at least 85% homologous to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, or SEQ ID NO:13. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V L Area, the V L The region has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homologous to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V L Area, the V L The region has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V L Area, the V L The region has the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, or any variant thereof having 1-10 substitutions, deletions or insertions. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V L Area, the V L The region has an amino acid sequence of SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13, or any variant thereof having 1-10 conservative substitutions. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V L Area, the V L The region has the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13.

[0011] In some embodiments, the antibody or antigen-binding fragment comprises: a heavy chain variable (VH ) region, the heavy chain variable region includes a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3), wherein the HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; the HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33. In some embodiments, the antibody or antigen-binding fragment thereof includes V H Area, the V H The antibody or antigen-binding fragment thereof comprises V H Area, the V H The antibody or antigen-binding fragment thereof comprises V H Area, the V H The antibody or antigen-binding fragment thereof comprises V H Area, the V H The region includes HCDR1, HCDR2 and HCDR3, wherein the HCDR1 has the amino acid sequence of SEQ ID NO:31; the HCDR2 has the amino acid sequence of SEQ ID NO:32; and the HCDR3 has the amino acid sequence of SEQ ID NO:33.

[0012] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises a heavy chain variable (V H) region, wherein the heavy chain variable region has an amino acid sequence that is at least 85% homologous to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, or SEQ ID NO:12. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V H Area, the V H The region has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homologous to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V H Area, the V H The region has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V H Area, the V H The region has the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, or any variant thereof having 1-10 substitutions, deletions or insertions. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V H Area, the V H The region has an amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, or any variant thereof having 1-10 conservative substitutions. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V H Area, the V H The region has the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12.

[0013] In some embodiments, the antibody or antigen-binding fragment comprises: (i) VL Area, the V L The region comprises LCDR1, LCDR2 and LCDR3, wherein the LCDR1 has an amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23; the LCDR2 has an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24; and the LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) V H Area, the V H The region includes HCDR1, HCDR2 and HCDR3, wherein the HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; the HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33.

[0014] In some embodiments, the antibody or antigen-binding fragment comprises: (i) V L Area, the V L The region comprises LCDR1, LCDR2 and LCDR3, wherein the LCDR1 has an amino acid sequence of SEQ ID NO: 17; the LCDR2 has an amino acid sequence of SEQ ID NO: 18; and the LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) V H Area, the V H The region includes HCDR1, HCDR2 and HCDR3, wherein the HCDR1 has the amino acid sequence of SEQ ID NO: 20; the HCDR2 has the amino acid sequence of SEQ ID NO: 21; and the HCDR3 has the amino acid sequence of SEQ ID NO: 22.

[0015] In some embodiments, the antibody or antigen-binding fragment comprises: (i) V L Area, the V L The region comprises LCDR1, LCDR2 and LCDR3, wherein the LCDR1 has an amino acid sequence of SEQ ID NO: 23; the LCDR2 has an amino acid sequence of SEQ ID NO: 24; and the LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) V H Area, the V HThe region includes HCDR1, HCDR2 and HCDR3, wherein the HCDR1 has the amino acid sequence of SEQ ID NO: 25; the HCDR2 has the amino acid sequence of SEQ ID NO: 26; and the HCDR3 has the amino acid sequence of SEQ ID NO: 27.

[0016] In some embodiments, the antibody or antigen-binding fragment comprises: (i) V L Area, the V L The region comprises LCDR1, LCDR2 and LCDR3, wherein the LCDR1 has an amino acid sequence of SEQ ID NO: 23; the LCDR2 has an amino acid sequence of SEQ ID NO: 24; and the LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) V H Area, the V H The region includes HCDR1, HCDR2 and HCDR3, wherein the HCDR1 has the amino acid sequence of SEQ ID NO:28; the HCDR2 has the amino acid sequence of SEQ ID NO:29; and the HCDR3 has the amino acid sequence of SEQ ID NO:30.

[0017] In some embodiments, the antibody or antigen-binding fragment comprises: (i) V L Area, the V L The region comprises LCDR1, LCDR2 and LCDR3, wherein the LCDR1 has an amino acid sequence of SEQ ID NO: 23; the LCDR2 has an amino acid sequence of SEQ ID NO: 24; and the LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) V H Area, the V H The region includes HCDR1, HCDR2 and HCDR3, wherein the HCDR1 has the amino acid sequence of SEQ ID NO:31; the HCDR2 has the amino acid sequence of SEQ ID NO:32; and the HCDR3 has the amino acid sequence of SEQ ID NO:33.

[0018] In some embodiments, the antibody or antigen-binding fragment comprises: (i) V L Area, the V L The region has an amino acid sequence of SEQ ID NO: 5, or a variant thereof; and (ii) V H Area, the V H The region has an amino acid sequence of SEQ ID NO: 4, or a variant thereof. In some embodiments, the antibody or antigen-binding fragment comprises: (i) V LArea, the V L The region has an amino acid sequence of SEQ ID NO: 7, or a variant thereof; and (ii) V H Area, the V H The region has an amino acid sequence of SEQ ID NO: 6, or a variant thereof. In some embodiments, the antibody or antigen-binding fragment comprises: (i) V L Area, the V L The region has an amino acid sequence of SEQ ID NO: 9, or a variant thereof; and (ii) V H Area, the V H The region has an amino acid sequence of SEQ ID NO: 8, or a variant thereof. In some embodiments, the antibody or antigen-binding fragment comprises: (i) V L Area, the V L The region has an amino acid sequence of SEQ ID NO: 11, or a variant thereof; and (ii) V H Area, the V H The region has an amino acid sequence of SEQ ID NO: 10, or a variant thereof. In some embodiments, the antibody or antigen-binding fragment comprises: (i) V L Area, the V L The region has the amino acid sequence of SEQ ID NO: 13, or a variant thereof; and (ii) V H Area, the V H The region has the amino acid sequence of SEQ ID NO: 12, or a variant thereof.

[0019] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises a V L Area and V H In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises a V region connected by a peptide linker. L Area and V H In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises a peptide linker comprising the sequence GQSSRSSGGGGSSGGGGS (SEQ ID NO: 14); (GGGGS) n (SEQ ID NO:15)(GGGGA) n (SEQ ID NO: 16) or any combination thereof, wherein each n is independently 1 to 5. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises a peptide linker that does not contain the sequence of GQSSRSSGGGGSSGGGGS (SEQ ID NO: 14).

[0020] In some embodiments, the antibody or antigen binding fragment thereof that binds to the claudin 18.2 protein additionally comprises at least one additional peptide that binds to a different target protein. In some embodiments, the antibody or antigen binding fragment thereof that binds to the claudin 18.2 protein additionally comprises at least one additional peptide that binds to a different target protein, wherein the different target protein is CD3 or CD28. In some embodiments, the antibody or antigen binding fragment thereof that binds to the claudin 18.2 protein additionally comprises at least one additional peptide that binds to a different target protein, wherein the at least one additional peptide is an antibody or antigen binding fragment.

[0021] In some embodiments, the antibody or antigen-binding fragment thereof binds to residues E56, N153, Y155, M158 and G159 of claudin 18.2 protein. In some embodiments, the antibody or antigen-binding fragment thereof binds to residues V40, E56, N153, Y155, M158, G159 and G160 of claudin 18.2 protein.

[0022] In some embodiments, a nucleic acid molecule is provided, which encodes an antibody or an antigen-binding fragment thereof that binds to claudin 18.2 protein as described herein.

[0023] In some embodiments, a vector is provided, comprising a nucleic acid molecule encoding an antibody or an antigen-binding fragment thereof that binds to claudin 18.2 protein as described herein.

[0024] In some embodiments, a cell is provided, the cell comprising a nucleic acid molecule encoding an antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein as described herein. In some embodiments, a cell is provided that comprises a vector, the vector comprising a nucleic acid molecule encoding an antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein as described herein.

[0025] In some embodiments, a pharmaceutical composition is provided, comprising an antibody or an antigen-binding fragment thereof that binds to the claudin protein 18.2 protein as described herein. In some embodiments, a pharmaceutical composition is provided, comprising a nucleic acid molecule encoding an antibody or an antigen-binding fragment thereof that binds to the claudin protein 18.2 protein as described herein. In some embodiments, a pharmaceutical composition comprising a carrier is provided, the carrier comprising a nucleic acid molecule encoding an antibody or an antigen-binding fragment thereof that binds to the claudin protein 18.2 protein as described herein. In some embodiments, the pharmaceutical composition is an injectable pharmaceutical composition. In some embodiments, the pharmaceutical composition is sterile or pyrogen-free. In some embodiments, the pharmaceutical composition does not contain an antibody or an antigen-binding fragment thereof that does not bind to claudin protein 18.2.

[0026] In some embodiments, a method for treating a subject with a tumor or gastric tumor is provided, the method comprising administering to the subject a therapeutically effective amount of a sealin 18.2 antibody or an antigen-binding fragment thereof as described herein. In some embodiments, a method for treating a subject with a tumor or gastric tumor is provided, the method comprising administering to the subject a therapeutically effective amount of a drug combination group comprising a sealin 18.2 antibody or an antigen-binding fragment thereof as described herein. In some embodiments, the tumor or gastric tumor is gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, pancreatic adenocarcinoma or non-small cell lung cancer. In some embodiments, the subject is a human, a mouse, a sheep, a rat, a rabbit, a shark, a llama or a chicken.

[0027] In some embodiments, a method for detecting the presence or absence of claudin 18.2 in a sample is provided, the method comprising contacting the sample with an antibody or an antigen-binding fragment thereof that binds to claudin 18.2 as described herein, and detecting the binding of the antibody or its antigen-binding fragment to the claudin 18.2 antigen, wherein the detection of binding indicates the presence of claudin 18.2; or the failure to detect binding to claudin 18.2 indicates the absence of claudin 18.2.

[0028] In some embodiments, a method of inducing an immune response against a claudin 18.2 protein in a subject is provided, the method comprising administering a virus-like particle comprising the claudin 18.2 protein to the subject under conditions sufficient to induce an immune response. In some embodiments, the subject is a human, mouse, sheep, rat, rabbit, shark, llama or chicken.

[0029] In some embodiments, a method for generating an antibody or antigen-binding fragment thereof that binds to a claudin 18.2 protein is provided. In some embodiments, a method for generating an antibody or antigen-binding fragment thereof that binds to a claudin 18.2 protein comprises administering to a subject a virus-like particle comprising a claudin 18.2 protein on its surface under conditions that induce an immune response to the claudin 18.2 protein. In some embodiments, the subject is a human, mouse, sheep, rat, rabbit, shark, llama, or chicken.

[0030] In some embodiments, the method for generating an antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein further comprises separating the antibody that binds to the claudin 18.2 protein. In some embodiments, the generated antibody or antigen-binding fragment thereof binds to the extracellular domain of the claudin 18.2 protein. In some embodiments, the method for generating an antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein further comprises generating virus-like particles comprising the claudin 18.2 protein. In some embodiments, the method for generating an antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein further comprises transfecting or transducing cells with the claudin 18.2 protein and the retroviral gag protein under conditions sufficient to produce virus-like particles comprising the claudin 18.2 protein. In some embodiments, the cell is a HEK-293T cell. In some embodiments, the gag protein is an MLV gag protein. In some embodiments, the retroviral gag protein is a murine leukemia virus (MLV), gag, HIV gag, or RSV gag protein.

[0031] In some embodiments, a method for regulating the activity of claudin 18.2 is provided. In some embodiments, the method for regulating the activity of claudin 18.2 comprises contacting a cell expressing claudin 18.2 with a claudin 18.2 antibody or its antigen-binding fragment that binds to claudin 18.2 on the cell surface. In some embodiments, the method for regulating the activity of claudin 18.2 comprises contacting a cell expressing claudin 18.2 with a pharmaceutical composition comprising a claudin 18.2 antibody or its antigen-binding fragment that binds to claudin 18.2 on the cell surface. In some embodiments, the method for regulating the activity of claudin 18.2 comprises administering to a subject an antibody or its antigen-binding fragment that binds to claudin 18.2 protein, as provided herein. In some embodiments, the method for regulating the activity of claudin 18.2 comprises administering to a subject a pharmaceutical composition comprising an antibody or its antigen-binding fragment that binds to claudin 18.2 protein, as provided herein.

[0032] In some embodiments, a chimeric antigen receptor is provided, wherein the chimeric antigen receptor comprises an extracellular portion, the extracellular portion comprising an antibody or antigen binding fragment thereof that binds to claudin 18.2, as provided herein. In some embodiments, a chimeric antigen receptor comprises an extracellular portion, the extracellular portion comprising an antibody or antigen binding fragment thereof that binds to claudin 18.2, as provided herein, wherein the antibody or antigen binding fragment thereof comprises a binding domain, and wherein the binding domain is a scFv fragment.

[0033] In some embodiments, a multispecific molecule is provided, wherein the multispecific molecule comprises a first portion or domain that binds to the claudin 18.2 protein, and a second portion or domain that binds to a second molecule. In some embodiments, the multispecific molecule has a therapeutic effect on cells expressing claudin 18.2. In some embodiments, the first portion or domain that binds to claudin 18.2 is an antibody or a binding fragment thereof, as provided herein. In some embodiments, the first portion or domain that binds to claudin 18.2 is an antibody or a binding fragment thereof comprising a binding domain, as provided herein, wherein the binding domain is an scFv fragment. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 The binding of three humanized antibodies against claudin 18.2, MAb1 (IM-44-09B03-1HB), MAb2 (IM-44-01E10-1HA), and MAb3 (IM-44-05H06-1HD), to cells expressing claudin 18.2 is shown. Figure 1 Also shown is a positive control, labeled "Clinical Benchmark."

[0035] Figure 2A The specificity of MAb1 (IM-44-09B03-1HB) for the human, cynomolgus and mouse forms of claudin 18.2 is shown.

[0036] Figure 2B The specificity of MAb2 (IM-44-01E10-1HA) for the human, cynomolgus and mouse forms of claudin 18.2 is shown.

[0037] Figure 2C Specificity of MAb3 (IM-44-05H06-1HD) for human, cynomolgus and mouse forms of claudin 18.2 is shown.

[0038] Figure 3A It was shown that the specificity of the humanized antibody MAb1 (IM-44-09B03-1HB) for claudin 18.2 is better than that for claudin 18.1. MAb1 (IM-44-09B03-1HB) showed no cross-reactivity for claudin 18.1.

[0039] Figure 3B It was shown that the specificity of the humanized antibody MAb2 (IM-44-01E10-1HA) for claudin 18.2 is better than that for claudin 18.1. MAb2 (IM-44-01E10-1HA) showed no cross-reactivity for claudin 18.1.

[0040] Figure 3CThe humanized antibody MAb3 (IM-44-05H06-1HD) showed better specificity against claudin 18.2 than against claudin 18.1. MAb3 (IM-44-05H06-1HD) showed no cross-reactivity against claudin 18.1.

[0041] Figure 4A Figure 2 shows the dissociation constant (K) of the humanized antibody MAb1 (IM-44-09B03-1HB) against claudin 18.2. D )'s exemplary biosensor data.

[0042] Figure 4B Figure 2 shows the dissociation constant (K) of the humanized antibody MAb2 (IM-44-01E10-1HA) against claudin 18.2. D )'s exemplary biosensor data.

[0043] Figure 4C Figure 2 shows the dissociation constant (K) of the humanized antibody MAb3 (IM-44-05H06-1HD) against claudin 18.2. D )'s exemplary biosensor data.

[0044] Figure 4D Depicted are the dissociation constants (K) used to determine the positive control. D ) which is labeled as “Clinical Benchmark” for claudin 18.2.

[0045] Figure 5A The residues of claudin 18.2 that are critical for binding of the humanized antibody MAb1 (IM-44-09B03-1HB) as determined by epitope mapping are shown.

[0046] Figure 5B The residues of claudin 18.2 that are critical for binding of the humanized antibody MAb2 (IM-44-01E10-1HA) as determined by epitope mapping are shown.

[0047] Figure 5C The residues of claudin 18.2 that are critical for binding of the humanized antibody MAb3 (IM-44-05H06-1HD) as determined by epitope mapping are shown.

[0048] Figure 5D The residues of claudin 18.2 that are critical for binding of the positive control ("clinical benchmark"; zolbetuximab) are shown, as determined by epitope mapping.

[0049] Fig. 6A Monovalent and bivalent binding of MAb1 are shown.

[0050] Figure 6B Monovalent and bivalent binding of MAb2 are shown.

[0051] Figure 6C Monovalent and bivalent binding of MAb3 are shown. DETAILED DESCRIPTION

[0052] Provided herein are antibodies or antigen binding fragments thereof that bind to the clamin 18.2 protein. In some embodiments, the antibody or antigen binding fragment thereof that binds to the clamin 18.2 protein is separated. In some embodiments, the antibody or antigen binding fragment thereof that binds to the clamin 18.2 protein is recombinant. In some embodiments, the antibody or antigen binding fragment thereof is a conformational MAb (monoclonal antibody) that recognizes the clamin 18.2 protein in its natural environment or natural structure. Without being bound by any particular theory, the clamin 18.2 protein in its natural environment or natural structure refers to the clamin 18.2 protein that is located in the plasma membrane (cell membrane) or in a bilayer structure. The natural structure of the clamin 18.2 protein in its natural environment can be folded so that the clamin 18.2 protein crosses the plasma membrane or lipid bilayer many times. Therefore, the antibody or antigen binding fragment thereof that binds to the clamin 18.2 protein in its natural environment or natural structure refers to the antibody or antigen binding fragment thereof that binds to the clamin 18.2 protein in the plasma membrane (cell membrane) or a bilayer structure. In some embodiments, the antibody or antigen-binding fragment thereof that binds to claudin 18.2 is specific to claudin 18.2 and does not cross-react with claudin 18.1 or does not significantly cross-react with claudin 18.1. Therefore, the present disclosure provides surprising and unexpected results, part of which is an antibody that can bind to claudin 18.2 in its native structure and / or its native environment without cross-reacting with claudin 18.1. In some embodiments, the antibody or antigen-binding fragment thereof that binds to claudin 18.2 inhibits the activity of claudin 18.2. In some embodiments, the antibody or antigen-binding fragment thereof that binds to claudin 18.2 recognizes a conformational epitope on native claudin 18.2 present in intact human cells. In some embodiments, the antibody or antigen-binding fragment thereof that binds to claudin 18.2 protein exhibits significant specificity within the claudin family, reacting with mouse orthologs, but not with most other members of the human membrane proteome. In some embodiments, the antibody or antigen-binding fragment thereof that binds to claudin 18.2 protein is MAbs MAb1 (IM-44-09B03-1HB), MAb2 (IM-44-01E10-1HA), or MAb3 (IM-44-05H06-1HD).

[0053] As used herein, the term "antibody" refers to any form of antibody that exhibits a desired biological activity. Therefore, it is used in the broadest sense and specifically covers, but is not limited to, monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized antibodies, fully human antibodies, chimeric antibodies, and camelized single domain antibodies. "Parent antibody" is an antibody obtained by exposing the immune system to an antigen before modifying the antibody for the intended use (such as humanization of the antibody for use as a human therapeutic antibody). In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein is a monoclonal antibody.

[0054] As used herein, unless otherwise indicated, "antibody fragment" or "antigen-binding fragment" refers to an antigen-binding fragment of an antibody, i.e., an antibody fragment that retains the ability to specifically bind to an antigen that binds to a full-length antibody, such as a fragment that retains one or more CDR regions. Examples of antibody-binding fragments include, but are not limited to, Fab, Fab', F(ab'), 2 and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules, such as sc-Fv; nanobodies and multispecific antibodies formed from antibody fragments.

[0055] The "Fab fragment" consists of a light chain and a heavy chain C H The heavy chain of a Fab molecule cannot form a disulfide bond with another heavy chain molecule.

[0056] The "Fc" region contains the C H 1 and C H The two heavy chain fragments are connected by two or more disulfide bonds and C H The 3 domains are held together by hydrophobic interactions.

[0057] The "Fab' fragment" contains a light chain and a V H Domain and C H 1 domain, and also contains a portion or fragment of a heavy chain of the C H 1 and C H The region between the two Fab domains allows interchain disulfide bonds to form between the two heavy chains of the two Fab' fragments to form F(ab') 2 molecular.

[0058] “F(ab') 2 The "fragment" comprises two light chains and two heavy chains, wherein the two heavy chains comprise C H 1 and C H 2 The portion of the constant region between the two heavy chains that allows for the formation of interchain disulfide bonds.2 The fragment consists of two Fab' fragments held together by a disulfide bond between the two heavy chains.

[0059] The "Fv region" includes the variable regions from the heavy and light chains, but lacks the constant regions.

[0060] The term "single-chain Fv" or "scFv" antibody refers to an antibody comprising a V H and V L The Fv polypeptide further comprises V H and V L A polypeptide linker between domains that enables scFv to form the structure required for antigen binding. For a review of scFv, see Pluckthun (1994) The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds. Springer-Verlag, New York, pp. 269-315. See also International Patent Application Publication No. WO 88 / 01649 and U.S. Patent Nos. 4,946,778 and 5,260,203. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein is an scFv antibody.

[0061] "Domain antibodies" are immunologically functional immunoglobulin fragments that contain only the variable region of a heavy chain or a light chain. H The two V domains of the bivalent domain antibody are covalently linked to a peptide linker to generate a bivalent domain antibody. H The regions can target the same or different antigens.

[0062] A "bivalent antibody" includes two antigen binding sites. In some cases, the two binding sites have the same antigen specificity. However, a bivalent antibody can be bispecific (see below).

[0063] In certain embodiments, the monoclonal antibodies described herein also include camelized single domain antibodies. See, e.g., Muyldermans et al. (2001) Trends Biochem. Sci. 26:230; Reichmann et al. (1999) J. Immunol. Methods 231:25; WO 94 / 04678; WO 94 / 25591; US ​​Pat. No. 6,005,079). In one embodiment, the present disclosure provides a monoclonal antibody comprising two V H domain single domain antibody, the two V HThe domains are modified to form single domain antibodies.

[0064] As used herein, the term "diabodies" refers to small antibody fragments with two antigen-binding sites comprised of two antigen-binding sites on the same polypeptide chain (V H -V L or V L -V H ) and the light chain variable domain (V L ) connected to the heavy chain variable domain (V H ). By using a linker that is too short to allow pairing between two domains on the same chain, these domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. Diabodies are more fully described in, for example, EP 404,097; WO 93 / 11161; and Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448. For a review of engineered antibody variants, see Holliger and Hudson (2005) Nat. Biotechnol. 23:1126-1136.

[0065] Typically, when the activity is expressed on a molar basis, the variant antibodies or antigen-binding fragments of the antibodies provided herein retain at least 10% of their claudin 18.2 binding activity (when compared to the modified parent antibody). In some embodiments, the variant antibodies (or their antigenic fragments) or antigen-binding fragments of the antibodies provided herein retain at least 20%, 50%, 70%, 80%, 90%, 95% or 100% or more of the claudin 18.2 binding affinity as the parent antibody. As described herein. It is also expected that the antibodies or their antigen-binding fragments disclosed herein may include conservative or non-conservative amino acid substitutions that do not substantially change their biological activity, which may also be referred to as "conservative variants" or "functional conservative variants" of antibodies.

[0066] "Isolated antibody" refers to the purified state of the binding compound, and in this case means that the molecule is substantially free of other biomolecules, such as nucleic acids, proteins, lipids, carbohydrates, or other materials, such as cell debris and growth medium. Generally, the term "isolated" does not mean the complete absence of such substances or the absence of water, buffers or salts, unless they are present in amounts that significantly interfere with the experimental or therapeutic use of the binding compounds described herein.

[0067] As used herein, the term "monoclonal antibody" refers to a substantially homogeneous antibody population, that is, the amino acid sequence of the antibody molecules comprising the population is identical except for possible naturally occurring mutations that may be present in small amounts. In contrast, conventional (polyclonal) antibody preparations typically include a variety of different antibodies whose variable domains (particularly their CDRs) have different amino acid sequences, which are typically specific for different epitopes. The modifier "monoclonal" indicates the characteristics of the antibody obtained by a substantially homogeneous antibody population, and should not be construed as requiring the production of antibodies by any particular method. For example, the monoclonal antibodies used in accordance with the present disclosure can be prepared by the hybridoma method first described by Kohler et al. (1975) Nature 256:495, or can be prepared by recombinant DNA methods (see, e.g., U.S. Patent No. 4,816,567). "Monoclonal antibodies" can also be isolated from phage antibody libraries using, for example, the techniques described in Clackson et al. (1991) Nature 352:624-628 and Marks et al. (1991) J. Mol. Biol. 222:581-597. See also Presta (2005) J. Allergy Clin. Immunol. 116:731.

[0068] As used herein, a "chimeric antibody" is an antibody having a variable domain from a first antibody and a constant domain from a second antibody, wherein the first and second antibodies are from different species. (U.S. Pat. No. 4,816,567; and Morrison et al., (1984) Proc. Natl. Acad. Sci. USA 81:6851-6855). Typically, the variable domains are obtained from antibodies ("parent antibodies") of experimental animals (such as rodents), and the constant domain sequences are obtained from human antibodies, so that the resulting chimeric antibodies will be less likely to elicit an adverse immune response in human subjects than the parent (e.g., rodent) antibodies.

[0069] As used herein, the term "humanized antibody" refers to an antibody form comprising sequences from human and non-human (e.g., mouse, rat) antibodies. Typically, a humanized antibody will include substantially at least one, and typically all of two variable domains, wherein all or substantially all hypervariable loops correspond to those of non-human immunoglobulins, and all or substantially all framework (FR) regions are those of human immunoglobulin sequences. A humanized antibody may optionally include at least a portion of a human immunoglobulin constant region (Fc). In some embodiments, an antibody or antigen-binding fragment thereof that binds to a claudin 18.2 protein is a humanized antibody.

[0070] The term "fully human antibody" refers to an antibody that includes only the protein sequence of human immunoglobulins. If the fully human antibody is produced in a mouse, a mouse cell, or a hybridoma derived from a mouse cell, it may contain a mouse carbohydrate chain. Similarly, a "mouse antibody" refers to an antibody that includes only mouse immunoglobulin sequences. Alternatively, if the fully human antibody is produced in a rat, a rat cell, or a hybridoma derived from a rat cell, it may contain a rat carbohydrate chain. Similarly, a "rat antibody" refers to an antibody that includes only rat immunoglobulin sequences. In some embodiments, the antibody or its antigen-binding fragment binds to human claudin 18.2 protein. In some embodiments, the antibody or its antigen-binding fragment that binds to claudin 18.2 protein is a chicken antibody. In some embodiments, the antibody or its antigenic fragment is generated by inducing an immune response to claudin 18.2 in a chicken.

[0071] Typically, the basic antibody structural unit comprises a tetramer. Each tetramer includes two pairs of identical polypeptide chains, each pair having a "light" chain (about 25 kDa) and a "heavy" chain (about 50-70 kDa). The amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids that is primarily responsible for antigen recognition. The carboxyl-terminal portion of the heavy chain can define a constant region that is primarily responsible for effector function. Typically, human light chains are classified as κ light chains and λ light chains. In addition, human heavy chains are typically classified as μ, δ, γ, α, or ε, and the isotypes of antibodies are defined as IgM, IgD, IgG, IgA, and IgE, respectively. Within the light and heavy chains, the variable and constant regions are connected by a "J" region of about 12 or more amino acids, and the heavy chain also includes a "D" region of about 10 or more amino acids. See generally Fundamental Immunology Ch.7 (Paul, W., ed., 2 nd ed. Raven Press, NY (1989).

[0072] The variable regions of each light / heavy chain pair form an antibody binding site. Thus, typically, an intact antibody has two binding sites. Except in bifunctional or bispecific antibodies, the two binding sites are typically identical.

[0073] Typically, the variable domains of the heavy and light chains include three hypervariable regions, also called complementarity determining regions (CDRs), which are located within relatively conserved framework regions (FRs). The CDRs are typically aligned through the framework regions to enable binding to specific epitopes. Typically, from the N-terminus to the C-terminus, both the light and heavy chain variable domains include FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The assignment of amino acids to each domain is typically based on the following definitions: Sequences of Proteins of Immunological Interest, Kabat, et al.; National Institutes of Health, Bethesda, Md.; 5 th ed.; NIHPubl. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32: 1-75; Kabat, et al., (1977) J. Biol. Chem. 252: 6609-6616; Chothia, et al., (1987) J Mol. Biol. 196:901-917 or Chothia, et al., (1989) Nature 342:878-883.

[0074] As used herein, the term "hypervariable region" refers to the amino acid residues of an antibody or antigen-binding fragment thereof that are responsible for antigen binding. The hypervariable region includes amino acid residues from the "complementarity determining region" or "CDR" (i.e., residues 24-34 (CDRL1), 50-56 (CDRL2), and 89-97 (CDRL3) in the light chain variable domain and residues 31-35 (CDRH1), 50-65 (CDRH2), and 95-102 (CDRH3) in the heavy chain variable domain; Kabat et al. (1991) Sequences of Proteins of Immunological Interest, 5 thEd. Public Health Service, National Institutes of Health, Bethesda, Md.) and / or those residues from the "hypervariable loops" (i.e., residues 26-32 (CDRL1), 50-52 (CDRL2), and 91-96 (CDRL3) in the light chain variable domain and 26-32 (CDRH1), 53-55 (CDRH2), and 96-101 (CDRH3) in the heavy chain variable domain; Chothia and Lesk (1987) J. Mol. Biol. 196:901-917). As used herein, the term "framework" or "FR" residues refers to those variable domain residues other than the hypervariable region residues defined herein as CDR residues. The CDRs provide most of the contact residues for antibody binding to an antigen or epitope. The CDRs of interest may be derived from donor antibody variable heavy and light chain sequences, and include analogs of naturally occurring CDRs that also share or retain the same antigen binding specificity and / or neutralizing ability as the donor antibody from which they are derived.

[0075] The term "chicken antibody" refers to an antibody produced in a chicken. For example, the target protein can be introduced into a chicken, such as into a VLP provided herein, to stimulate an immune response against the target protein, thereby producing antibodies in a chicken. The antibody can then be humanized or otherwise modified as needed.

[0076] In addition, in some embodiments, the antibody or antigen-binding fragment thereof can be in the following forms: full-length antibody, single domain antibody, recombinant heavy chain antibody only (VHC), single chain antibody (scFv), shark heavy chain antibody only (VNAR), microprotein (cysteine ​​knot protein, knottin), DARPin; Tetranectin; Affibody; Transbody; Anticalin; AdNectin; Affilin; Microbody; Peptide aptamer; alterase; Plastic antibody; phylomer; stradobody; maxibody; evibody; fynomer, armadillo repeat protein, Kunitz domain, avimer, atrimer, probody, immunobody, triomab, troybody; pepbody; vaccibody, UniBody; Affimer, DuoBody, Fv, Fab, Fab', F(ab')2, peptide mimetic molecule or synthetic molecule, such as U.S. Patent No. or Patent Publication No. US 7,417,130, US2004 / 132094, US 5,831,012, US2004 / 023334, US 7,250,297, US 6,818,418, US2004 / 209243, US 7,838,629, US 7,186,524, US 6,004,746, US 5,475,096, US2004 / 146938, US2004 / 157209, US 6,994,982, US6,794,144, US2010 / 239633, US 7,803,907, US2010 / 119446 and / or US 7,166,697, the contents of each of which are incorporated herein by reference in their entirety. See also Storz MAbs. 2011 May-Jun; 3(3):310-317, which is hereby incorporated by reference.

[0077] The term "antigen" as used herein means any molecule with the ability to generate antibodies directly or indirectly. The definition of "antigen" includes nucleic acids encoding proteins. "Antigen" can also refer to the binding partner of an antibody. In some embodiments, the antigen is a sealing protein 18.2 protein expressed on the surface of a cell or particle (such as a virus-like particle). In some embodiments, the cell is a complete cell. A complete cell is a cell that has not been lysed or broken using a detergent or other reagent. Cells that have been treated with detergents or other reagents that destroy the cell membrane or punch holes in the cell membrane are not complete cells. By expressing receptors on the surface of cells or particles (such as liposome particles (lipoparticle)), receptors can present conformational epitopes, which may not exist if purified proteins are used. Examples are provided herein. In some embodiments, adjuvants are not used, but adjuvants can be used. In some embodiments, particles are injected into poultry (such as chickens) to stimulate an immune response and generate antibodies to proteins present on the particle surface. Particles suitable for generating antibodies and methods for preparing them are described, for example, in U.S. Patent Nos. 8,377,691, 7,763,258, 8,158,130 and U.S. Patent Application Publication Nos. 20050123563 and 20120195882, each of which is incorporated herein by reference. These publications and patents describe the generation of various particles (including liposome nanoparticles) that can be used to express transmembrane proteins (e.g., multi-transmembrane proteins, ion channels, etc.). In some embodiments, sealin 18.2 can be incorporated into lipid particles according to these methods or as provided herein.

[0078] For example, the present invention provides a method for generating an antibody or antigen-binding fragment thereof that binds to a claudin 18.2 protein, the method comprising administering a virus-like particle comprising a claudin 18.2 protein on its surface to a subject under conditions that induce an immune response to the claudin 18.2 protein, to generate an antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein. In some embodiments, a nucleic acid molecule encoding a claudin 18.2 protein is provided.

[0079] In some embodiments, the method further comprises separating antibodies or antigen-binding fragments thereof that bind to the claudin 18.2 protein. In some embodiments, the subject is a human, mouse, sheep, rat, rabbit, shark, llama or chicken. In some embodiments, the generated antibody or antigen-binding fragment thereof binds to the extracellular domain of the claudin 18.2 protein. In some embodiments, the method comprises generating virus-like particles comprising the claudin 18.2 protein, the method comprising transfecting or transducing cells with the claudin 18.2 protein and the gag protein under conditions sufficient to produce virus-like particles comprising the claudin 18.2 protein. VLPs can be generated as described herein and in the above-mentioned references. In some embodiments, the cell is a HEK-293T cell. In some embodiments, the gag protein is a retroviral gag protein. In some embodiments, the retroviral gag protein is a murine leukemia virus (MLV) gag protein. In some embodiments, Gag is HIV. In some embodiments, Gag is Rous sarcoma virus Gag.

[0080] As used herein, "specific binding" or "immunospecific binding" or "immunospecifically binding" refers to the binding of an antibody or antibody fragment to a predetermined antigen (e.g., claudin 18.2) or an epitope present on an antigen. In some embodiments, the antibody or antigen-binding fragment thereof is expressed in an amount of 10 -7 M or less dissociation constant (K D ) and binds to a nonspecific antigen other than the predetermined antigen (e.g., BSA, casein, or another nonspecific polypeptide) at a higher K than that of the nonspecific antigen. D At least twice smaller than K D Binds to a predetermined antigen. The phrases "antibodies that recognize cladin 18.2" and "cladin 18.2-specific antibodies" may be used interchangeably herein with the term "antibodies that immunospecifically bind to cladin 18.2." Reference may be made to cladin 18.2 in the present disclosure. In some embodiments, the antibody or its antigen-binding fragment specifically binds to cladin 18.2 and not to other proteins, such as but not limited to cladin 18.1. The degree of specificity required for anti-cladin 18.2 antibodies or their antigen-binding fragments may depend on the intended use of the antibody and is in any case limited by its suitability for the intended purpose. In some embodiments, the antibody of the envisioned method or a binding compound derived from the antigen-binding site of the antibody binds to its antigen (cladin 18.2) with an affinity that is at least twice as great, at least ten times as great, at least 20 times as great, or at least 100 times as great as the affinity of any other antigen.

[0081] Methods for determining mAb specificity and affinity by competitive inhibition can be found in Harlow, et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1988), Colligan et al., eds., Current Protocols in Immunology, Greene Publishing Assoc. and Wiley Interscience, NY, (1992, 1993), and Muller, Meth. Enzymol. 92:589 601 (1983), which are incorporated herein by reference in their entireties.

[0082] The term "homolog" means a protein sequence with 40% to 100% sequence homology or identity to a reference sequence. The percent identity between two peptide chains can be determined by pairwise alignment using the default settings of the AlignX module of Vector NTI v.9.0.0 (Invitrogen Corp., Carslbad, Calif.). In some embodiments, the antibody or its antigen-binding fragment has at least 50, 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% homology or identity to the sequence described herein. In some embodiments, the antibody or its antigen-binding fragment has conservative substitutions compared to the sequence described herein. Exemplary conservative substitutions are shown in Table 1 and are covered within the scope of the disclosed subject matter. As long as the properties of the antibody are not adversely affected, conservative substitutions can be located in the framework region or the antigen binding site. Substitutions can be performed to improve antibody properties, such as stability or affinity. Conservative substitutions will produce molecules with functions and chemical features similar to those of molecules subjected to such modifications. Exemplary amino acid substitutions are shown in the table below.

[0083]

[0084]

[0085] In some embodiments, variants of proteins and peptides provided herein are provided. In some embodiments, variants include displacement, deletion or insertion. In some embodiments, variants include 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 (e.g., 1-10) displacements. As described herein, displacement can be a conservative displacement. In some embodiments, displacement is non-conservative. In some embodiments, variants include 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 (e.g., 1-10) deletions. In some embodiments, variants include 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 (e.g., 1-10) insertions. In some embodiments, there is displacement, deletion or insertion in CDR provided herein. In some embodiments, there is no displacement, deletion or insertion in CDR provided herein.

[0086] As used herein, the term "in combination with" means that the described agents can be administered to an animal or subject together in the form of a mixture, simultaneously as single agents, or sequentially in any order as single agents.

[0087] Techniques for producing antibodies to small peptide sequences are well known in the art, and these antibodies recognize and bind to those small peptide sequences in free or conjugated form or when presented as native sequences in the context of large proteins. Such antibodies include mouse, mouse-human, and human-human antibodies produced by hybridomas or recombinant techniques known in the art. Antibodies can also be produced in humans, mice, sheep, rats, rabbits, sharks, llamas, or chickens. In some embodiments, antibodies or antigen-binding fragments thereof are produced in chickens. Antibodies can also be produced in other small animals.

[0088] The term "epitope" means the part of any molecule that can be recognized and bound by an antibody or its antigen binding fragment at one or more antigen binding regions. An epitope is usually composed of chemically active surface groups of molecules (such as amino acids or sugar side chains) and has specific three-dimensional structural characteristics and specific charge characteristics. Examples of epitopes include, but are not limited to, the residues described herein that form the claudin 18.2 epitope. In some embodiments, the epitope is only present in non-denatured proteins. In some embodiments, the epitope is only present in denatured proteins.

[0089] In some embodiments, the source of DNA encoding a non-human antibody or antigen-binding fragment thereof includes an antibody-producing cell line, such as a hybrid cell line commonly referred to as a hybridoma.

[0090] Hybrid cells are formed by the fusion of non-human antibody producing cells, typically spleen cells of animals immunized against natural or recombinant antigens or peptide fragments of antigenic protein sequences. Alternatively, the non-human antibody producing cells can be B lymphocytes obtained from the blood, spleen, lymph nodes or other tissues of animals immunized with antigens.

[0091] The second fusion partner providing the immortalization function can be a lymphoblastoid cell or plasmacytoma or myeloma cell, which is not itself an antibody producing cell, but is malignant. Fusion partner cells include, but are not limited to, hybridoma SP2 / 0-Ag14 (abbreviated as SP2 / 0 (ATCC CRL1581)) and myeloma P3X63Ag8 (ATCC TIB9) or derivatives thereof. See, for example, Ausubel below, Harlow below, and Colligan below, the contents of which are fully incorporated herein by reference.

[0092] Antibodies can be generated according to the examples provided herein. Once the sequence is known, antibodies can also be generated according to known methods. Antibodies can also be converted into different types, such as converted into human IgG, etc. By converting antibodies into human antibodies, human subjects should not recognize antibodies as foreign. The conversion of non-human IgG antibodies to human IgG antibodies is well known, and can be routinely performed once the native sequence is known. As discussed herein, antibodies can be modified according to known methods. Such methods are described, for example, in: Riechmann L, Clark M, Waldmann H, Winter G (1988). Reshaping human antibodies for therapy". Nature 332(6162): 332–323; Tsurushita N, Park M, Pakabunto K, Ong K, Avdalovic A, Fu H, Jia A, Vásquez M, Kumar S. (2004); and "Humanization of a chicken anti-IL-12 monoclonal antibody" Immunol Methods 295(1-2): 9-19; Nishibori N, Horiuchi H, Furusawa S, Matsuda H. (2006) "Humanization of chicken monoclonal antibody using phage display system" Mol Immunol. 43(6): 634-42, each of which is incorporated by reference in its entirety.

[0093] The antibody producing cells contributing the nucleotide sequence of the antigen binding region encoding the chimeric antibody can also be produced by transforming non-human (such as primates) or human cells. For example, the B lymphocytes producing antibodies can be infected and transformed by viruses (such as Epstein-Barr virus) to produce immortalized antibody producing cells (Kozbor et al., Immunol. Today 4: 72 79 (1983)). Alternatively, as well known in the art, B lymphocytes can be transformed by providing a transforming gene or a transforming gene product. See, for example, Ausubel below, Harlow below, and Colligan below, the content of the document is fully incorporated herein by reference. Cell fusion is completed by standard procedures known to technicians in the field of immunology. Fusion partner cell lines and methods for fusion and selection of hybridomas and screening mAbs are well known in the art. See, for example, Ausubel below, Harlow below, and Colligan below, the content of the document is fully incorporated herein by reference.

[0094] In some embodiments, the antibody or antigen-binding fragment thereof is a MAb that binds to claudin 18.2. In some embodiments, the antibody or antigen-binding fragment thereof binds to amino acids of an epitope of claudin 18.2.

[0095] In some embodiments, the antibodies or antigen-binding fragments thereof comprise a sequence provided herein.

[0096] The sequence of the antibody can be modified to produce human IgG antibodies. The conversion of the sequence provided herein can be modified to produce other types of antibodies. The CDR can also be connected to other antibodies, proteins or molecules to produce antibody fragments that bind to sealin 18.2. This can be in the form of antibody drug conjugates ("ADC"), multispecific molecules or chimeric antigen receptors. The CDR and antibody sequences provided herein are also humanized or prepared into fully human according to known methods. The sequence can also be prepared into chimeric antibodies as described herein.

[0097] In some embodiments, the antibody or its antigen-binding fragment comprises an amino acid sequence comprising a sequence or fragment thereof provided herein. In some embodiments, the antibody or its antigen-binding fragment comprises one or more amino acid sequences, its antigen-binding fragment or its human IgG variant provided herein. "Its human IgG variant" refers to an antibody that has been modified to human IgG when the starting antibody is not a human IgG antibody.

[0098] As described herein, the production of antibodies with known sequences is conventional and can be carried out by any method. Therefore, in some embodiments, nucleic acids encoding antibodies or antigen-binding fragments thereof are provided. In some embodiments, nucleic acid encoding sequences provided herein. Antibodies can also be modified to chimeric antibodies or human antibodies. Antibodies can also be used in injectable pharmaceutical compositions. In addition, as described herein, antibodies can be isolated antibodies or engineered antibodies.

[0099] In some embodiments, "derivatives" of antibodies, antibody fragments, regions or derivatives thereof are provided, the term including those proteins encoded by truncated or modified genes to produce molecular species functionally similar to immunoglobulin fragments. Modifications include, but are not limited to, the addition of gene sequences encoding cytotoxic proteins such as plant and bacterial toxins. Modifications may also include reporter proteins such as fluorescent or chemiluminescent tags. Antibody fragments and derivatives may be produced in any manner.

[0100] Identification of these antigen binding regions and / or epitopes recognized by the Abs described herein provides the information necessary to generate additional monoclonal antibodies with similar binding characteristics and therapeutic or diagnostic utility similar to the embodiments of the present application.

[0101] The nucleic acid sequence encoding the antibody or its antigen-binding fragment described herein can be genomic DNA or cDNA, or RNA (e.g., mRNA) encoding at least one variable region described herein. A convenient alternative to using chromosomal gene fragments as a source of DNA encoding V region antigen-binding segments is to use cDNA to construct chimeric immunoglobulin genes, for example, as reported by Liu et al. (Proc. Natl. Acad. Sci., USA 84: 3439 (1987) and J. Immunology 139: 3521 (1987), which are incorporated herein by reference in their entirety. Using cDNA requires combining gene expression elements suitable for host cells with genes to achieve the synthesis of desired proteins. Using cDNA sequences is advantageous over genomic sequences (which contain introns) because cDNA sequences can be expressed in bacteria or other hosts lacking appropriate RNA splicing systems.

[0102] For example, it is possible to provide a cDNA encoding a V region antigen binding segment capable of detecting, combining or neutralizing a clam protein 18.2 antigen based on the amino acid sequence provided herein using known methods. Because the genetic code is degenerate, more than one codon can be used to encode a specific amino acid (Watson et al., see below). Using the genetic code, one or more different oligonucleotides can be identified, each of which will be able to encode an amino acid. In fact, the probability that a specific oligonucleotide will constitute an actual XXX encoding sequence can be estimated by considering the frequency of abnormal base pairing relationships and specific codons actually used (encoding specific amino acids) in eukaryotic or prokaryotic cells expressing antibodies or antibody fragments. Such "codon usage rules" are disclosed by Lathe, et al., J.Molec.Biol.183:1 12 (1985). Using Lathe's "codon usage rules", a single oligonucleotide or a group of oligonucleotides containing a theoretically "most likely" nucleotide sequence capable of encoding an antibody variable region or constant region sequence is identified.

[0103] The variable regions described herein can be combined with any type of constant region, including human constant regions or mouse constant regions. Human genes encoding constant (C) regions of antibodies, antibody fragments, and regions can be derived from human fetal liver libraries by known methods. Human C region genes can be derived from any human cell, including those that express and produce human immunoglobulins. Human C H The C region may be derived from any of the known classes or isotypes of human H chains, including γ, μ, α, δ, or ε and subtypes thereof, such as G1, G2, G3, and G4. Since H chain isotypes are responsible for various effector functions of antibodies, the C H The choice of region will be guided by the activity of the desired effector function, such as complement fixation or antibody-dependent cellular cytotoxicity (ADCC). H The region is derived from γ1 (IgG1), γ3 (IgG3), γ4 (IgG4) or μ (IgM). Human C LThe region may be derived from human L chain isotype κ or λ. In some embodiments, the antibody or its antigen-binding fragment comprises an Fc domain. In some embodiments, the Fc domain comprises mutations to extend the half-life of the antibody. In some embodiments, the Fc domain comprises mutations, such as those described in U.S. Patent No. 7,670,600, which is hereby incorporated herein by reference in its entirety. In some embodiments, according to the EU numbering index numbering of Kabat, relative to the wild-type human IgG constant domain, the constant region comprises a mutation at the position of amino acid residue 428. Without being bound by any particular theory, compared to the half-life of IgG with a wild-type human IgG constant domain, an antibody comprising a mutation corresponding to residue 428 may have an extended half-life. In some embodiments, the mutation is to replace a natural residue with threonine, leucine, phenylalanine or serine. In some embodiments, the antibody or antigen-binding fragment thereof further comprises one or more amino substitutions at one or more of amino acid residues 251-256, 285-290, 308-314, 385-389, and 429-436 relative to the corresponding wild-type human IgG constant domain, numbered according to the Kabat EU numbering index. Specific mutations or substitutions at these positions are described in U.S. Patent No. 7,670,600, which is hereby incorporated by reference in its entirety.

[0104] The gene encoding the human immunoglobulin C region can be obtained from human cells by standard cloning techniques (Sambrook, et al. (Molecular Cloning: A Laboratory Manual, 2 nd Edition, Cold Spring Harbor Press, Cold Spring Harbor, NY (1989) and Ausubel et al., eds. Current Protocols in Molecular Biology (1987 1993)). Human C region genes are readily obtained from known clones containing genes representing two classes of L chains, five classes of H chains and their subclasses. Chimeric antibody fragments, such as F(ab') 2 and Fab, can be prepared by designing appropriately truncated chimeric H chain genes. For example, encoding F(ab') 2 The chimeric gene for the H chain portion of the fragment will include the CH encoding the H chain 1 The DNA sequence of the structural domain and hinge region is followed by a translation stop codon to produce a truncated molecule.

[0105] In some embodiments, the antibodies, murine, human, humanized or chimeric antibodies, antibody fragments and antibody regions described herein are produced by cloning DNA segments encoding the H and L chain antigen binding regions of claudin 18.2 antigen-specific antibodies and combining these DNA segments with the C H and C L DNA segments of the same region can be joined to produce murine, human, or chimeric immunoglobulin encoding genes.

[0106] Thus, in some embodiments, a fusion chimeric gene is produced that includes at least a first DNA segment encoding an antigen-binding region of non-human origin, such as a functionally rearranged V region having a joining (J) segment, which is connected to a second DNA segment encoding at least a portion of a human C region.

[0107] Thus, cDNA encoding the V and C regions of the antibody, the method for producing antibodies according to some embodiments described herein involves several steps, as exemplified below: 1. Isolating messenger RNA (mRNA) from a cell line producing an anti-sealing protein 18.2 antigen antibody and from an optional additional antibody providing heavy and light constant regions; cloning and producing cDNA therefrom; 2. Preparing a full-length cDNA library from the purified mRNA, from which the appropriate V and / or C region gene segments of the L and H chain genes can be subjected to the following: (i) identification with appropriate probes, (ii) sequencing, and (iii) compatibility with the C or V gene segments of another antibody of the chimeric antibody; 3. Constructing a complete H or L chain coding sequence by connecting the cloned specific V region gene segment to the cloned C region gene as described above; 4. Expressing and producing the L and H chains in a selected host (including prokaryotic and eukaryotic cells) to provide mouse-mouse, human-mouse, human-human or human-mouse antibodies.

[0108] Two coding DNA sequences are said to be "operably linked" if the linkage results in a continuous translatable sequence without altering or interrupting the triplet reading frame. A DNA coding sequence is operably linked to a gene expression element if the linkage results in the correct function of the gene expression element to result in expression of the coding sequence.

[0109] As used herein, and unless otherwise indicated, the term "about" is intended to mean ±5% of its modified value. Thus, about 100 means 95 to 105.

[0110] In some embodiments, the antibodies or antigen-binding fragments thereof described herein are used to detect the presence of an antigen. The antibodies or antigen-binding fragments thereof can be used in any device or method to detect the presence of an antigen.

[0111] The term "purified" with respect to an antibody or antigen-binding fragment thereof refers to an antibody or antigen-binding fragment thereof that is substantially free of other substances associated with the molecule in its natural environment. For example, a purified protein is substantially free of cellular material or other proteins from the cell or tissue from which it is derived. The term refers to a preparation in which the isolated protein is pure enough for analysis, or at least 70% to 80% (w / w) pure, at least 80%-90% (w / w) pure, 90-95% pure; and, at least 95%, 96%, 97%, 98%, 99% or 100% (w / w) pure. In some embodiments, the antibody or antigen-binding fragment thereof is purified.

[0112] As an alternative to preparing monoclonal antibody secreting hybridomas, monoclonal antibodies against polypeptides can be identified and isolated by screening recombinant combinatorial immunoglobulin libraries (e.g., antibody phage display libraries) using the polypeptides described herein to separate immunoglobulin library members that bind to the polypeptides. Techniques and commercially available kits for generating and screening phage display libraries are well known to those skilled in the art. In addition, examples of methods and reagents particularly suitable for generating and screening antibody or antigen-binding protein display libraries can be found in the literature. Therefore, the epitopes described herein can be used to screen other antibodies that can be used therapeutically, diagnostically, or as research tools.

[0113] The antibodies provided herein can also be conjugated with a chemical moiety. The chemical moiety can be a polymer, a radionuclide or a cytotoxic factor in particular. In some embodiments, this can be referred to as an antibody drug conjugate. In some embodiments, the chemical moiety is a polymer that prolongs the half-life of the antibody molecule in the subject. Suitable polymers include, but are not limited to, polyethylene glycol (PEG) (e.g., a PEG with a molecular weight of 2kDa, 5kDa, 10kDa, 12kDa, 20kDa, 30kDa or 40kDa), dextran and monomethoxy polyethylene glycol (mPEG). Lee, et al., (1999) (Bioconj. Chem. 10: 973-981) discloses a single-chain antibody conjugated with PEG. Wen, et al., (2001) (Bioconj. Chem. 12: 545-553) discloses a conjugated antibody with a PEG attached to a radiometal chelator (diethylenetriaminepentaacetic acid (DTPA)). Examples of chemical moieties include, but are not limited to, anti-mitotic agents such as calicheamicin (e.g., ozogamicin), monomethyl auristatin E, mertansine, and the like. Other examples include, but are not limited to, biologically active anti-microtubule agents, alkylating agents, and DNA minor groove binders. Other examples are provided herein and below. The chemical moiety can be attached to the antibody by a linker (maleimide), a cleavable linker (such as a cathepsin cleavable linker (valine-citrulline), and in some embodiments, one or more spacers (e.g., p-aminobenzyl carbamate). Without being bound by any particular theory, once the antibody conjugate binds to claudin 18.2, it can be internalized, and the chemical moiety can kill the cell or otherwise inhibit its growth. In some embodiments, the cell is a gastric tumor cell.

[0114] The antibodies and antibody fragments of the present disclosure may also be conjugated to: tags such as 99 Tc, 90 Y. 111 In, 32 P. 14 C. 125 I. 3 H. 131 I. 11 C. 15 O. 13 N. 18 F. 35 S. 51 Cr, 57 To, 226 Ra, 60 Co. 59Fe, 57 Se, 152 Eu, 67 CU, 217 Ci, 211 At 212 Pb, 47 Sc, 109 Pd, 234 Th and 40 K. 157 Gd, 55 Mn, 52 Tr and 56 Fe.

[0115] Antibodies and antibody fragments may also be conjugated to fluorescent or chemiluminescent labels, including fluorophores such as rare earth chelates, fluorescein and its derivatives, rhodamine and its derivatives, isothiocyanates, phycoerythrin, phycocyanin, allophycocyanin, o-phthalaldehyde, fluorescamine, 152 Eu, dansyl, umbelliferone, fluorescein, luminal tags, isoluminol tags, acridinium ester tags, imidazole tags, acridimium salt tags, oxalate tags, aequorin tags, 2,3-dihydrophthalazinedione, biotin / avidin, spin tags, and stable free radicals.

[0116] The antibody or antibody fragment molecule can also be conjugated to cytotoxic factors such as diphtheria toxin, Pseudomonas aeruginosa exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins and compounds (e.g., fatty acids), dianthin proteins, Phytoiacca americana proteins PAPI, PAPII and PAP-S, momordica charantia inhibitor, curcin, crotin, saponaria officinalis inhibitor, mitogens, restrictocins, phenomycins and enomycins.

[0117] Any method known in the art for conjugating the antibodies or antibody molecules of the present disclosure to various moieties may be employed, including methods described by: Hunter, et al., (1962) Nature 144:945; David, et al., (1974) Biochemistry 13:1014; Pain, et al., (1981) J. Immunol. Meth. 40:219 and Nygren, J., (1982) Histochem. and Cytochem. 30:407. Methods for conjugating antibodies are routine and well known in the art.

[0118] The antibodies provided herein can also be incorporated into chimeric antigen receptors ("CAR"), which can be used, for example, in CAR-T cells. In some embodiments, the extracellular domain of CAR can be an antibody or antigen binding fragment thereof as provided herein. In some embodiments, the antibody or antigen binding fragment thereof is in the form of scFv. CAR-T cells are a type of therapy in which the patient's T cells are modified to enable them to attack cancer cells. T cells are taken from the patient's blood. Genes of specific receptors that bind to a certain protein on the patient's cancer cells are then added in the laboratory. In some embodiments, the receptor binds to clamin 18.2 using the binding region of the antibody provided herein. CAR-T cells including clamin 18.2 antibodies or antigen binding fragments thereof can then be used to treat tumors or gastric tumors, such as those described herein.

[0119] As used herein, the term "recombinant antibody" refers to an antibody that does not occur naturally. In some embodiments, the term "recombinant antibody" refers to an antibody that is not isolated from a human subject.

[0120] In some embodiments, provided herein is an antibody (e.g., an anti-sealant protein 18.2 antibody) or an antigen-binding fragment thereof. In some embodiments, the antibody or its antigen-binding fragment is a recombinant antibody that binds to the sealant protein 18.2 protein. In some embodiments, the antibody or its antigen-binding fragment that binds to the sealant protein 18.2 protein is a monoclonal antibody. In some embodiments, the antibody or its antigen-binding fragment that binds to the sealant protein 18.2 protein is a humanized antibody. In some embodiments, the antibody or its antigen-binding fragment that binds to the sealant protein 18.2 protein is a chicken antibody. In some embodiments, the antibody or its antigen-binding fragment is generated by inducing an immune response to the sealant protein 18.2 in chickens. In some embodiments, the antibody or its antigen-binding fragment that binds to the sealant protein 18.2 protein is a scFv antibody.

[0121] In some embodiments, the antibody or its antigen-binding fragment binds to human claudin 18.2 protein. In some embodiments, the antibody or its antigen-binding fragment recognizes claudin 18.2 protein in its native (non-denatured) conformation. In some embodiments, the antibody or its antigen-binding fragment does not specifically bind to denatured claudin 18.2 protein. In some embodiments, the antibody or its antigen-binding fragment binds to claudin 18.2 protein comprising the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3.

[0122]

[0123]

[0124] In some embodiments, the antibody or antigen-binding fragment thereof does not specifically bind claudin 18.1.

[0125] In some embodiments, the antibody or antigen-binding fragment thereof comprises a peptide having an amino acid sequence selected from the following table.

[0126]

[0127] In some embodiments, the antibody or antigen-binding fragment comprises a light chain comprising a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3). In some embodiments, the antibody or antigen-binding fragment comprises a light chain variable (V) comprising LCDR1, LCDR2, and LCDR3. L ) region. In some embodiments, the antibody or antigen-binding fragment comprises a light chain variable (V L ) region, the light chain variable region including LCDR1, LCDR2 and LCDR3.

[0128] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3). In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable (V ) comprising HCDR1, HCDR2, and HCDR3. H ) region. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable (V H ) region, the heavy chain variable region including HCDR1, HCDR2 and HCDR3.

[0129] In some embodiments, the antibody or its antigen-binding fragment comprises a light chain CDR or a heavy chain CDR having the following amino acid sequence: SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, or SEQ ID NO:33.

[0130] Different CDR motifs can be combined in any combination, including those not described in the above table. For example, the following embodiments are provided as non-limiting examples of such combinations.

[0131] In some embodiments, the antibody or antigen-binding fragment thereof comprises a light chain CDR having the following sequence: SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 23, or SEQ ID NO: 24. In some embodiments, the antibody or antigen-binding fragment comprises: a light chain variable (V) comprising LCDR1, LCDR2, and LCDR3; L ) region, wherein LCDR1 has the amino acid sequence of SEQ ID NO:17 or SEQ ID NO:23; LCDR2 has the amino acid sequence of SEQ ID NO:18 or SEQ ID NO:24; and the LCDR3 sequence has the amino acid sequence of SEQ ID NO:19.

[0132] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain CDR having the following sequence: SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, or SEQ ID NO: 33. In some embodiments, the antibody or antigen-binding fragment comprises: a heavy chain variable (V CDR) comprising HCDR1, HCDR2, and HCDR3; H) region, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33.

[0133] In some embodiments, the antibody or antigen-binding fragment thereof comprises a light chain having LCDR1, LCDR2, and LCDR3, wherein LCDR1 has the sequence of SEQ ID NO:17, LCDR2 has the sequence of SEQ ID NO:18, and LCDR3 has the sequence of SEQ ID NO:19.

[0134] In some embodiments, the antibody or antigen-binding fragment thereof comprises a light chain having LCDR1, LCDR2, and LCDR3, wherein LCDR1 has the sequence of SEQ ID NO:17, LCDR2 has the sequence of SEQ ID NO:24, and LCDR3 has the sequence of SEQ ID NO:19.

[0135] In some embodiments, the antibody or antigen-binding fragment thereof comprises a light chain having LCDR1, LCDR2, and LCDR3, wherein LCDR1 has the sequence of SEQ ID NO:23, LCDR2 has the sequence of SEQ ID NO:18, and LCDR3 has the sequence of SEQ ID NO:19.

[0136] In some embodiments, the antibody or antigen-binding fragment thereof comprises a light chain having LCDR1, LCDR2, and LCDR3, wherein LCDR1 has the sequence of SEQ ID NO:23, LCDR2 has the sequence of SEQ ID NO:24, and LCDR3 has the sequence of SEQ ID NO:19.

[0137] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:20, HCDR2 has the sequence of SEQ ID NO:21, and HCDR3 has the sequence of SEQ ID NO:22.

[0138] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:20, HCDR2 has the sequence of SEQ ID NO:21, and HCDR3 has the sequence of SEQ ID NO:27.

[0139] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:20, HCDR2 has the sequence of SEQ ID NO:21, and HCDR3 has the sequence of SEQ ID NO:30.

[0140] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:20, HCDR2 has the sequence of SEQ ID NO:21, and HCDR3 has the sequence of SEQ ID NO:33.

[0141] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:20, HCDR2 has the sequence of SEQ ID NO:26, and HCDR3 has the sequence of SEQ ID NO:22.

[0142] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:20, HCDR2 has the sequence of SEQ ID NO:26, and HCDR3 has the sequence of SEQ ID NO:27.

[0143] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:20, HCDR2 has the sequence of SEQ ID NO:26, and HCDR3 has the sequence of SEQ ID NO:30.

[0144] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:20, HCDR2 has the sequence of SEQ ID NO:26, and HCDR3 has the sequence of SEQ ID NO:33.

[0145] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:20, HCDR2 has the sequence of SEQ ID NO:29, and HCDR3 has the sequence of SEQ ID NO:22.

[0146] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:20, HCDR2 has the sequence of SEQ ID NO:29, and HCDR3 has the sequence of SEQ ID NO:27.

[0147] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:20, HCDR2 has the sequence of SEQ ID NO:29, and HCDR3 has the sequence of SEQ ID NO:30.

[0148] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:20, HCDR2 has the sequence of SEQ ID NO:29, and HCDR3 has the sequence of SEQ ID NO:33.

[0149] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:20, HCDR2 has the sequence of SEQ ID NO:32, and HCDR3 has the sequence of SEQ ID NO:22.

[0150] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:20, HCDR2 has the sequence of SEQ ID NO:32, and HCDR3 has the sequence of SEQ ID NO:27.

[0151] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:20, HCDR2 has the sequence of SEQ ID NO:32, and HCDR3 has the sequence of SEQ ID NO:30.

[0152] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:20, HCDR2 has the sequence of SEQ ID NO:32, and HCDR3 has the sequence of SEQ ID NO:33.

[0153] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:25, HCDR2 has the sequence of SEQ ID NO:21, and HCDR3 has the sequence of SEQ ID NO:22.

[0154] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:25, HCDR2 has the sequence of SEQ ID NO:21, and HCDR3 has the sequence of SEQ ID NO:27.

[0155] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:25, HCDR2 has the sequence of SEQ ID NO:21, and HCDR3 has the sequence of SEQ ID NO:30.

[0156] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:25, HCDR2 has the sequence of SEQ ID NO:21, and HCDR3 has the sequence of SEQ ID NO:33.

[0157] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:25, HCDR2 has the sequence of SEQ ID NO:26, and HCDR3 has the sequence of SEQ ID NO:22.

[0158] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:25, HCDR2 has the sequence of SEQ ID NO:26, and HCDR3 has the sequence of SEQ ID NO:27.

[0159] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:25, HCDR2 has the sequence of SEQ ID NO:26, and HCDR3 has the sequence of SEQ ID NO:30.

[0160] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:25, HCDR2 has the sequence of SEQ ID NO:26, and HCDR3 has the sequence of SEQ ID NO:33.

[0161] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:25, HCDR2 has the sequence of SEQ ID NO:29, and HCDR3 has the sequence of SEQ ID NO:22.

[0162] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:25, HCDR2 has the sequence of SEQ ID NO:29, and HCDR3 has the sequence of SEQ ID NO:27.

[0163] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:25, HCDR2 has the sequence of SEQ ID NO:29, and HCDR3 has the sequence of SEQ ID NO:30.

[0164] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:25, HCDR2 has the sequence of SEQ ID NO:29, and HCDR3 has the sequence of SEQ ID NO:33.

[0165] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:25, HCDR2 has the sequence of SEQ ID NO:32, and HCDR3 has the sequence of SEQ ID NO:22.

[0166] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:25, HCDR2 has the sequence of SEQ ID NO:32, and HCDR3 has the sequence of SEQ ID NO:27.

[0167] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:25, HCDR2 has the sequence of SEQ ID NO:32, and HCDR3 has the sequence of SEQ ID NO:30.

[0168] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:25, HCDR2 has the sequence of SEQ ID NO:32, and HCDR3 has the sequence of SEQ ID NO:33.

[0169] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:28, HCDR2 has the sequence of SEQ ID NO:21, and HCDR3 has the sequence of SEQ ID NO:22.

[0170] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:28, HCDR2 has the sequence of SEQ ID NO:21, and HCDR3 has the sequence of SEQ ID NO:27.

[0171] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:28, HCDR2 has the sequence of SEQ ID NO:21, and HCDR3 has the sequence of SEQ ID NO:30.

[0172] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:28, HCDR2 has the sequence of SEQ ID NO:21, and HCDR3 has the sequence of SEQ ID NO:33.

[0173] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:28, HCDR2 has the sequence of SEQ ID NO:26, and HCDR3 has the sequence of SEQ ID NO:22.

[0174] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:28, HCDR2 has the sequence of SEQ ID NO:26, and HCDR3 has the sequence of SEQ ID NO:27.

[0175] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:28, HCDR2 has the sequence of SEQ ID NO:26, and HCDR3 has the sequence of SEQ ID NO:30.

[0176] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:28, HCDR2 has the sequence of SEQ ID NO:26, and HCDR3 has the sequence of SEQ ID NO:33.

[0177] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:28, HCDR2 has the sequence of SEQ ID NO:29, and HCDR3 has the sequence of SEQ ID NO:22.

[0178] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:28, HCDR2 has the sequence of SEQ ID NO:29, and HCDR3 has the sequence of SEQ ID NO:27.

[0179] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:28, HCDR2 has the sequence of SEQ ID NO:29, and HCDR3 has the sequence of SEQ ID NO:30.

[0180] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:28, HCDR2 has the sequence of SEQ ID NO:29, and HCDR3 has the sequence of SEQ ID NO:33.

[0181] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:28, HCDR2 has the sequence of SEQ ID NO:32, and HCDR3 has the sequence of SEQ ID NO:22.

[0182] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:28, HCDR2 has the sequence of SEQ ID NO:32, and HCDR3 has the sequence of SEQ ID NO:27.

[0183] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:28, HCDR2 has the sequence of SEQ ID NO:32, and HCDR3 has the sequence of SEQ ID NO:30.

[0184] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:28, HCDR2 has the sequence of SEQ ID NO:32, and HCDR3 has the sequence of SEQ ID NO:33.

[0185] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:31, HCDR2 has the sequence of SEQ ID NO:21, and HCDR3 has the sequence of SEQ ID NO:22.

[0186] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:31, HCDR2 has the sequence of SEQ ID NO:21, and HCDR3 has the sequence of SEQ ID NO:27.

[0187] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:31, HCDR2 has the sequence of SEQ ID NO:21, and HCDR3 has the sequence of SEQ ID NO:30.

[0188] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:31, HCDR2 has the sequence of SEQ ID NO:21, and HCDR3 has the sequence of SEQ ID NO:33.

[0189] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:31, HCDR2 has the sequence of SEQ ID NO:26, and HCDR3 has the sequence of SEQ ID NO:22.

[0190] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:31, HCDR2 has the sequence of SEQ ID NO:26, and HCDR3 has the sequence of SEQ ID NO:27.

[0191] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:31, HCDR2 has the sequence of SEQ ID NO:26, and HCDR3 has the sequence of SEQ ID NO:30.

[0192] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:31, HCDR2 has the sequence of SEQ ID NO:26, and HCDR3 has the sequence of SEQ ID NO:33.

[0193] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:31, HCDR2 has the sequence of SEQ ID NO:29, and HCDR3 has the sequence of SEQ ID NO:22.

[0194] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:31, HCDR2 has the sequence of SEQ ID NO:29, and HCDR3 has the sequence of SEQ ID NO:27.

[0195] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:31, HCDR2 has the sequence of SEQ ID NO:29, and HCDR3 has the sequence of SEQ ID NO:30.

[0196] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:31, HCDR2 has the sequence of SEQ ID NO:29, and HCDR3 has the sequence of SEQ ID NO:33.

[0197] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:31, HCDR2 has the sequence of SEQ ID NO:32, and HCDR3 has the sequence of SEQ ID NO:22.

[0198] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:31, HCDR2 has the sequence of SEQ ID NO:32, and HCDR3 has the sequence of SEQ ID NO:27.

[0199] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:31, HCDR2 has the sequence of SEQ ID NO:32, and HCDR3 has the sequence of SEQ ID NO:30.

[0200] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having HCDR1, HCDR2, and HCDR3, wherein HCDR1 has the sequence of SEQ ID NO:31, HCDR2 has the sequence of SEQ ID NO:32, and HCDR3 has the sequence of SEQ ID NO:33.

[0201] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0202] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0203] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0204] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0205] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0206] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0207] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0208] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0209] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0210] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0211] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0212] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0213] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0214] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0215] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0216] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0217] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0218] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0219] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0220] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0221] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0222] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0223] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0224] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0225] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0226] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0227] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0228] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0229] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0230] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0231] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0232] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0233] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0234] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0235] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0236] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0237] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0238] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0239] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0240] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0241] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0242] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0243] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0244] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0245] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0246] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0247] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0248] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0249] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0250] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0251] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0252] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0253] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0254] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0255] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0256] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0257] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0258] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0259] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0260] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0261] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0262] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0263] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0264] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0265] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0266] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0267] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0268] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0269] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0270] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0271] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0272] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0273] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0274] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0275] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0276] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0277] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0278] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0279] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0280] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0281] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0282] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0283] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0284] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0285] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0286] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0287] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0288] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0289] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0290] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0291] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0292] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0293] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0294] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0295] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0296] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0297] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0298] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0299] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0300] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0301] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0302] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0303] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0304] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0305] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0306] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0307] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0308] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0309] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0310] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0311] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0312] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0313] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0314] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0315] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0316] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0317] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0318] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0319] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0320] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0321] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0322] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0323] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0324] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0325] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0326] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0327] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0328] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0329] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0330] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0331] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0332] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0333] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0334] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0335] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0336] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0337] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0338] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0339] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0340] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0341] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0342] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0343] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0344] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0345] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0346] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0347] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0348] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0349] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0350] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0351] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0352] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0353] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0354] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0355] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0356] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0357] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0358] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0359] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0360] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0361] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0362] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0363] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0364] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0365] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0366] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0367] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0368] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0369] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0370] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0371] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0372] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0373] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0374] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0375] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0376] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0377] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0378] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0379] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0380] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0381] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0382] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0383] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0384] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0385] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0386] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0387] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0388] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0389] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0390] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0391] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0392] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0393] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0394] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0395] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0396] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0397] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0398] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0399] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0400] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0401] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0402] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0403] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0404] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0405] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0406] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0407] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0408] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 20; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0409] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0410] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0411] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0412] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0413] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0414] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0415] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0416] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0417] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0418] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0419] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0420] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0421] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0422] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0423] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0424] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 25; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0425] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0426] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0427] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0428] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0429] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0430] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0431] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0432] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0433] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0434] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0435] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0436] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0437] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0438] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0439] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0440] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 28; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0441] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0442] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0443] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0444] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 21; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0445] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0446] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0447] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0448] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 26; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0449] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0450] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0451] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0452] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 29; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0453] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 22.

[0454] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 27.

[0455] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 30.

[0456] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO: 31; HCDR2 has an amino acid sequence of SEQ ID NO: 32; and HCDR3 has an amino acid sequence of SEQ ID NO: 33.

[0457] In some embodiments, the antibody or antigen-binding fragment thereof comprises one or more peptides having the following amino acid sequence: SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12 or SEQ ID NO:13, or a variant thereof.

[0458]

[0459]

[0460] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises a light chain variable (V L ) region, the light chain variable region having an amino acid sequence that is at least 85% homologous to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, provided that V L The region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO:17 or SEQ ID NO:23; LCDR2 has an amino acid sequence of SEQ ID NO:18 or SEQ ID NO:24; and LCDR3 has an amino acid sequence of SEQ ID NO:19.

[0461] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises V L Area, the V LThe region has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homologous to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, provided that V L The region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO:17 or SEQ ID NO:23; LCDR2 has an amino acid sequence of SEQ ID NO:18 or SEQ ID NO:24; and LCDR3 has an amino acid sequence of SEQ ID NO:19.

[0462] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises V L Area, the V L The region has an amino acid sequence that is at least 90% homologous to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, provided that V L The region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V L Area, the V L The region has an amino acid sequence that is at least 91% homologous to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, provided that V L The region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V L Area, the V LThe region has an amino acid sequence that is at least 92% homologous to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, provided that V L The region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V L Area, the V L The region has an amino acid sequence that is at least 93% homologous to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, provided that V L The region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V L Area, the V L The region has an amino acid sequence that is at least 94% homologous to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, provided that V L The region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V L Area, the V L The region has an amino acid sequence that is at least 95% homologous to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, provided that VL The region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V L Area, the V L The region has an amino acid sequence that is at least 96% homologous to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, provided that V L The region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V L Area, the V L The region has an amino acid sequence that is at least 97% homologous to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, provided that V L The region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V L Area, the V L The region has an amino acid sequence that is at least 98% homologous to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, provided that V LThe region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V L Area, the V L The region has an amino acid sequence that is at least 99% homologous to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, provided that V L The region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO:17 or SEQ ID NO:23; LCDR2 has an amino acid sequence of SEQ ID NO:18 or SEQ ID NO:24; and LCDR3 has an amino acid sequence of SEQ ID NO:19.

[0463] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises V L Area, the V L The region has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, provided that V L The region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO:17 or SEQ ID NO:23; LCDR2 has an amino acid sequence of SEQ ID NO:18 or SEQ ID NO:24; and LCDR3 has an amino acid sequence of SEQ ID NO:19.

[0464] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises V L Area, the V L The region has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, provided that V LThe region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V L Area, the V L The region has an amino acid sequence that is at least 91% identical to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, provided that V L The region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V L Area, the V L The region has an amino acid sequence that is at least 92% identical to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, provided that V L The region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V L Area, the V L The region has an amino acid sequence that is at least 93% identical to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, provided that V LThe region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V L Area, the V L The region has an amino acid sequence that is at least 94% identical to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, provided that V L The region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V L Area, the V L The region has an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, provided that V L The region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V L Area, the V L The region has an amino acid sequence that is at least 96% identical to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, provided that V LThe region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V L Area, the V L The region has an amino acid sequence that is at least 97% identical to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, provided that V L The region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V L Area, the V L The region has an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, provided that V L The region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V L Area, the V L The region has an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, provided that V LThe region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO:17 or SEQ ID NO:23; LCDR2 has an amino acid sequence of SEQ ID NO:18 or SEQ ID NO:24; and LCDR3 has an amino acid sequence of SEQ ID NO:19.

[0465] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises V L Area, the V L The region has the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, or any variant thereof having 1 to 10 substitutions, deletions or insertions, provided that V L The region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO:17 or SEQ ID NO:23; LCDR2 has an amino acid sequence of SEQ ID NO:18 or SEQ ID NO:24; and LCDR3 has an amino acid sequence of SEQ ID NO:19.

[0466] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises V L Area, the V L The region has the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, or any variant thereof having 1-10 conservative substitutions, provided that V L The region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO:17 or SEQ ID NO:23; LCDR2 has an amino acid sequence of SEQ ID NO:18 or SEQ ID NO:24; and LCDR3 has an amino acid sequence of SEQ ID NO:19.

[0467] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises V L Area, the V L The region has the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13.

[0468] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises V L Area, the V L The region has the amino acid sequence of SEQ ID NO: 5, or a variant thereof, provided that V L The region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO:17; LCDR2 has an amino acid sequence of SEQ ID NO:18; and LCDR3 has an amino acid sequence of SEQ ID NO:19.

[0469] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises V L Area, the V L The region has the amino acid sequence of SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, or a variant thereof, provided that V L The region includes LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO:23; LCDR2 has an amino acid sequence of SEQ ID NO:24; and LCDR3 has an amino acid sequence of SEQ ID NO:19.

[0470] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises a heavy chain variable (V H ) region, the heavy chain variable region having an amino acid sequence that is at least 85% homologous to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, provided that V H The region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33.

[0471] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises V H Area, the V HThe region has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homologous to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, provided that V H The region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33.

[0472] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises V H Area, the V H The region has an amino acid sequence that is at least 90% homologous to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, provided that V H The region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V H Area, the V H The region has an amino acid sequence that is at least 91% homologous to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, provided that V HThe region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V H Area, the V H The region has an amino acid sequence that is at least 92% homologous to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, provided that V H The region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V H Area, the V H The region has an amino acid sequence that is at least 93% homologous to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, provided that V HThe region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V H Area, the V H The region has an amino acid sequence that is at least 94% homologous to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, provided that V H The region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V H Area, the V H The region has an amino acid sequence that is at least 95% homologous to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, provided that V HThe region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V H Area, the V H The region has an amino acid sequence that is at least 96% homologous to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, provided that V H The region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V H Area, the V H The region has an amino acid sequence that is at least 97% homologous to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, provided that V HThe region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V H Area, the V H The region has an amino acid sequence that is at least 98% homologous to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, provided that V H The region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V H Area, the V H The region has an amino acid sequence that is at least 99% homologous to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, provided that V HThe region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33.

[0473] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises V H Area, the V H The region has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, provided that V H The region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33.

[0474] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises V H Area, the V H The region has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, provided that V HThe region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V H Area, the V H The region has an amino acid sequence that is at least 91% identical to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, provided that V H The region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V H Area, the V H The region has an amino acid sequence that is at least 92% identical to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, provided that V HThe region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V H Area, the V H The region has an amino acid sequence that is at least 93% identical to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, provided that V H The region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V H Area, the V H The region has an amino acid sequence that is at least 94% identical to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, provided that V HThe region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V H Area, the V H The region has an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, provided that V H The region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V H Area, the V H The region has an amino acid sequence that is at least 96% identical to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, provided that V HThe region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V H Area, the V H The region has an amino acid sequence that is at least 97% identical to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, provided that V H The region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V H Area, the V H The region has an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, provided that V HThe region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein includes V H Area, the V H The region has an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, provided that V H The region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33.

[0475] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises V H Area, the V H The region has the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, or any variant thereof having 1 to 10 substitutions, deletions or insertions, provided that V HThe region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33.

[0476] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises V H Area, the V H The region has the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, or any variant thereof having 1-10 conservative substitutions, provided that V H The region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 sequence has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33.

[0477] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises a V having an amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, or SEQ ID NO: 12. H district.

[0478] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises V H Area, the V H The region has the amino acid sequence of SEQ ID NO: 4, or a variant thereof, provided that V HThe region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20; HCDR2 has an amino acid sequence of SEQ ID NO:21; and HCDR3 has an amino acid sequence of SEQ ID NO:22.

[0479] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises V H Area, the V H The region has the amino acid sequence of SEQ ID NO: 6 or SEQ ID NO: 8, or a variant thereof, provided that V H The region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:25; HCDR2 has an amino acid sequence of SEQ ID NO:26; and HCDR3 has an amino acid sequence of SEQ ID NO:27.

[0480] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises V H Area, the V H The region has the amino acid sequence of SEQ ID NO: 10, or a variant thereof, provided that V H The region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:28; HCDR2 has an amino acid sequence of SEQ ID NO:29; and HCDR3 has an amino acid sequence of SEQ ID NO:30.

[0481] In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises a V having an amino acid sequence of SEQ ID NO: 12. H region or a variation thereof, provided that the V H The region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:32; and HCDR3 has an amino acid sequence of SEQ ID NO:33.

[0482] In some embodiments, the antibody or antigen-binding fragment thereof comprises SEQ ID NO: 4 and SEQ ID NO: 5 or the CDR regions thereof.

[0483] In some embodiments, the antibody or antigen-binding fragment thereof comprises SEQ ID NO: 6 and SEQ ID NO: 7 or the CDR regions thereof.

[0484] In some embodiments, the antibody or antigen-binding fragment thereof comprises SEQ ID NO: 8 and SEQ ID NO: 9 or the CDR regions thereof.

[0485] In some embodiments, the antibody or antigen-binding fragment thereof comprises SEQ ID NO: 10 and SEQ ID NO: 11 or the CDR regions thereof.

[0486] In some embodiments, the antibody or antigen-binding fragment thereof comprises SEQ ID NO: 12 and SEQ ID NO: 13 or the CDR regions thereof.

[0487] In some embodiments, the antibody or antigen-binding fragment comprises: (i) V L Area, the V L The region comprises LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) V H Area, the V H The region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and HCDR3 has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:33.

[0488] In some embodiments, the antibody or antigen-binding fragment comprises: (i) V L Area, the V L The region has the amino acid sequence of SEQ ID NO: 5, or a variant thereof, provided that V L The region comprises LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 17; LCDR2 has an amino acid sequence of SEQ ID NO: 18; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) V H Area, the V H The region has the amino acid sequence of SEQ ID NO: 4, or a variant thereof, provided that V HThe region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:20; HCDR2 has an amino acid sequence of SEQ ID NO:21; and HCDR3 has an amino acid sequence of SEQ ID NO:22.

[0489] In some embodiments, the antibody or antigen-binding fragment comprises: (i) V L Area, the V L The region has the amino acid sequence of SEQ ID NO: 7, or a variant thereof, provided that V L The region comprises LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) V H Area, the V H The region has the amino acid sequence of SEQ ID NO: 6, or a variant thereof, provided that V H The region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:25; HCDR2 has an amino acid sequence of SEQ ID NO:26; and HCDR3 has an amino acid sequence of SEQ ID NO:27.

[0490] In some embodiments, the antibody or antigen-binding fragment comprises: (i) V L Area, the V L The region has the amino acid sequence of SEQ ID NO: 9, or a variant thereof, provided that V L The region comprises LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) V H Area, the V H The region has the amino acid sequence of SEQ ID NO: 8, or a variant thereof, provided that V H The region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:25; HCDR2 has an amino acid sequence of SEQ ID NO:26; and HCDR3 has an amino acid sequence of SEQ ID NO:27.

[0491] In some embodiments, the antibody or antigen-binding fragment comprises: (i) V L Area, the VL The region has the amino acid sequence of SEQ ID NO: 11, or a variant thereof, provided that V L The region comprises LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) V H Area, the V H The region has the amino acid sequence of SEQ ID NO: 10, or a variant thereof, provided that V H The region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:28; HCDR2 has an amino acid sequence of SEQ ID NO:29; and HCDR3 has an amino acid sequence of SEQ ID NO:30.

[0492] In some embodiments, the antibody or antigen-binding fragment comprises: (i) V L Area, the V L The region has the amino acid sequence of SEQ ID NO: 13, or a variant thereof, provided that V L The region comprises LCDR1, LCDR2 and LCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) V H Area, the V H The region has the amino acid sequence of SEQ ID NO: 12, or a variant thereof, provided that V H The region includes HCDR1, HCDR2 and HCDR3, wherein HCDR1 has an amino acid sequence of SEQ ID NO:31; HCDR2 has an amino acid sequence of SEQ ID NO:32; and HCDR3 has an amino acid sequence of SEQ ID NO:33.

[0493] In some embodiments, LCDR1 is replaced by any one of other LCDR1 sequences. In some embodiments, LCDR2 is replaced by any one of other LCDR2 sequences. In some embodiments, LCDR3 is replaced by any one of other LCDR3 sequences. In some embodiments, HCDR1 is replaced by any one of other LCDR1 sequences. In some embodiments, HCDR2 is replaced by any one of other LCDR2 sequences. In some embodiments, HCDR3 is replaced by any one of other LCDR3 sequences.

[0494] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where V H The region includes the sequence of SEQ ID NO: 4 and V L The region includes the sequence of SEQ ID NO:5.

[0495] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where V H The region includes the sequence of SEQ ID NO: 4 and V L The region includes the sequence of SEQ ID NO:7.

[0496] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where V H The region includes the sequence of SEQ ID NO: 4 and V L The region includes the sequence of SEQ ID NO:9.

[0497] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where V H The region includes the sequence of SEQ ID NO: 4 and V L The region includes the sequence of SEQ ID NO:11.

[0498] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where V H The region includes the sequence of SEQ ID NO: 4 and V L The region includes the sequence of SEQ ID NO:13.

[0499] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where V H The region includes the sequence of SEQ ID NO: 6 and V L The region includes the sequence of SEQ ID NO:5.

[0500] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where V H The region includes the sequence of SEQ ID NO: 6 and V L The region includes the sequence of SEQ ID NO:7.

[0501] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where V H The region includes the sequence of SEQ ID NO: 6 and V L The region includes the sequence of SEQ ID NO:9.

[0502] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where V H The region includes the sequence of SEQ ID NO: 6 and V L The region includes the sequence of SEQ ID NO:11.

[0503] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where V H The region includes the sequence of SEQ ID NO: 6 and V L The region includes the sequence of SEQ ID NO:13.

[0504] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where V H The region includes the sequence of SEQ ID NO: 8 and V L The region includes the sequence of SEQ ID NO:5.

[0505] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where V H The region includes the sequence of SEQ ID NO: 8 and V L The region includes the sequence of SEQ ID NO:7.

[0506] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where V H The region includes the sequence of SEQ ID NO: 8 and V L The region includes the sequence of SEQ ID NO:9.

[0507] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where V H The region includes the sequence of SEQ ID NO: 8 and VL The region includes the sequence of SEQ ID NO:11.

[0508] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where V H The region includes the sequence of SEQ ID NO: 8 and V L The region includes the sequence of SEQ ID NO:13.

[0509] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where V H The region includes the sequence of SEQ ID NO: 10 and V L The region includes the sequence of SEQ ID NO:5.

[0510] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where V H The region includes the sequence of SEQ ID NO: 10 and V L The region includes the sequence of SEQ ID NO:7.

[0511] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where V H The region includes the sequence of SEQ ID NO: 10 and V L The region includes the sequence of SEQ ID NO:9.

[0512] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where V H The region includes the sequence of SEQ ID NO: 10 and V L The region includes the sequence of SEQ ID NO:11.

[0513] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where V H The region includes the sequence of SEQ ID NO: 10 and V L The region includes the sequence of SEQ ID NO:13.

[0514] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where VH The region includes the sequence of SEQ ID NO: 12 and V L The region includes the sequence of SEQ ID NO:5.

[0515] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where V H The region includes the sequence of SEQ ID NO: 12 and V L The region includes the sequence of SEQ ID NO:7.

[0516] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where V H The region includes the sequence of SEQ ID NO: 12 and V L The region includes the sequence of SEQ ID NO:9.

[0517] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where V H The region includes the sequence of SEQ ID NO: 12 and V L The region includes the sequence of SEQ ID NO:11.

[0518] In some embodiments, the antibody or antigen-binding fragment thereof comprises V H Area and V L Area, where V H The region includes the sequence of SEQ ID NO: 12 and V L The region includes the sequence of SEQ ID NO:13.

[0519] Apart from these specific combinations, any V H Area and V L Zones can be combined with each other.

[0520] In some embodiments, the antibody or antigen-binding fragment thereof comprises a peptide having an amino acid sequence as shown in any one of SEQ ID NOs: 4-13 and SEQ ID NOs: 17-33.

[0521] In some embodiments, the antibody or antigen-binding fragment thereof comprises a sequence or variant of any of the foregoing.

[0522] In some embodiments, the antibody or antigen-binding fragment thereof comprises a variant of the amino acid sequence of SEQ ID NO:4, 5, 6, 7, 8, 9, 10, 11, 12 or 13.

[0523] VL and V H The sequence may be in any form, including but not limited to L and V H As provided herein, the different variable regions (V H or V L ) can be connected with a peptide linker or not connected with a peptide linker but connected with a continuous sequence. Examples of peptide linkers that can be used to connect the various peptides provided herein include, but are not limited to: GQSSRSSGGGGSSGGGGS (SEQ ID NO: 14); (GGGGS) n (SEQ ID NO: 15); (GGGGA) n (SEQ ID NO: 16), or any combination thereof, wherein each n is independently 1-5. In some embodiments, the variable region is connected to a peptide linker. In some embodiments, the peptide linker comprises the sequence GQSSRSSGGGGSSGGGGS (SEQ ID NO: 14); (GGGGS) n (SEQ ID NO: 15); (GGGGA) n (SEQ ID NO: 16), or any combination thereof, wherein each n is independently 1-5. The linked peptide form can be represented by formula V H -ZV L or V L -ZV H In some embodiments, Z is GQSSRSSGGGGSSGGGGS (SEQ ID NO: 14); (GGGGS) n (SEQ ID NO: 15); (GGGGA) n (SEQ ID NO: 16), or any combination thereof, wherein each n is independently 1-5. In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises a peptide linker that does not contain the sequence GQSSRSSGGGGSSGGGGS (SEQ ID NO: 14). In some embodiments, the antibody or antigen-binding fragment thereof that binds to the claudin 18.2 protein comprises a peptide linker that does not contain (GGGGS) n (SEQ ID NO: 15); (GGGGA) n (SEQ ID NO: 16) or any combination thereof, wherein each n is independently 1 to 5. In some embodiments, the variable region is not linked to a peptide linker.

[0524] In some embodiments, the antibody or antigen-binding fragment thereof comprises a variant of the amino acid sequence of SEQ ID NO: 14, 15 or 16.

[0525] In addition, as provided herein, the antibody can be a multispecific antibody, in that the antibody can have multiple binding regions that target different proteins or the same protein at different epitopes. In some embodiments, the antibody or antigen-binding fragment thereof is a bispecific anti-CD3 x anti-CLDN 18.2 antibody or a trispecific anti-CD3 x anti-CD28 x anti-CLDN 18.2 antibody.

[0526] In some embodiments, the antibody or antigen-binding fragment thereof binds to residues E56, N153, Y155, M158 and G159 of claudin 18.2 protein. In some embodiments, the antibody or antigen-binding fragment thereof binds to residues V40, E56, N153, Y155, M158, G159 and G160 of claudin 18.2 protein.

[0527] In some embodiments, a nucleic acid molecule encoding an antibody or antigen-binding fragment thereof that binds to claudin 18.2 protein as described herein is provided.

[0528] In some embodiments, a vector comprising a nucleic acid molecule encoding an antibody or antigen-binding fragment thereof that binds to claudin 18.2 protein as described herein is provided.

[0529] In some embodiments, cells are provided that include a nucleic acid molecule encoding an antibody or antigen-binding fragment thereof that binds to a claudin 18.2 protein as described herein. In some embodiments, cells are provided that include a vector that includes a nucleic acid molecule encoding an antibody or antigen-binding fragment thereof that binds to a claudin 18.2 protein as described herein.

[0530] Pharmaceutical composition

[0531] In some embodiments, a pharmaceutical composition is provided that includes an antibody or antigen-binding fragment thereof that binds to claudin 18.2 protein as described herein.

[0532] In some embodiments, a pharmaceutical composition comprising a nucleic acid molecule encoding an antibody or antigen-binding fragment thereof that binds to a claudin 18.2 protein as described herein is provided.

[0533] In some embodiments, a pharmaceutical composition is provided that includes a vector that includes a nucleic acid molecule encoding an antibody or an antigen-binding fragment thereof that binds to a claudin 18.2 protein as described herein.

[0534] In some embodiments, to prepare a pharmaceutical composition or sterile pharmaceutical composition of an anti-claudin 18.2 antibody or other protein provided herein, the antibody or antigen-binding fragment thereof or other protein provided herein is blended with a pharmaceutically acceptable carrier or excipient. See, for example, Remington's Pharmaceutical Sciences and U.S. Pharmacopeia: National Formulary, Mack Publishing Company, Easton, PA (1984).

[0535] Formulations of therapeutic and diagnostic agents can be prepared by mixing with acceptable carriers, excipients or stabilizers in the form of, for example, lyophilized powders, slurries, aqueous solutions or suspensions (see, e.g., Hardman, et al. (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, NY; Avis, et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Forms: Disperse Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, NY). In some embodiments, the antibody is diluted to an appropriate concentration in a sodium acetate solution at pH 5-6, and NaCl or sucrose is added to maintain tonicity. Additional agents such as polysorbate 20 or polysorbate 80 may be added to enhance stability.

[0536] Toxicity and therapeutic efficacy of a pharmaceutical composition, administered alone or in combination with another agent, can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, to determine the LD 50 (lethal dose for 50% of the population) and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index (LD 50 / ED 50 ). In certain aspects, antibodies that exhibit high therapeutic indices are desirable. The data obtained from these cell culture assays and animal studies can be used to formulate a range of dosages for use in humans. The dosage of such compounds is preferably within the range of ED with little or no toxicity. 50 The dosage can vary within this range depending on the dosage form and route of administration used.

[0537] In some embodiments, the pharmaceutical compositions of the present disclosure are administered to a subject in accordance with the Physicians' Desk Reference 2003 (Thomson Healthcare; 57th edition (November 1, 2002)).

[0538] The mode of administration may vary. Suitable routes of administration include oral, rectal, transmucosal, enteral, parenteral; intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, directly intraventricular, intravenous, intraperitoneal, intranasal, intraocular, inhalation, insufflation, topical, dermal, transdermal or intraarterial.

[0539] In some embodiments, the antibody or its antigen binding fragment or its pharmaceutical composition can be administered by an invasive route such as by injection. In some embodiments, the antibody or its antigen binding fragment or its pharmaceutical composition is administered intravenously, subcutaneously, intramuscularly, intraarterially, intraarterially (e.g., in arthritic joints), intratumorally, or by inhalation, aerosol delivery. Administration by non-invasive routes (e.g., oral; e.g., in pills, capsules, or tablets) is also within the scope of embodiments of the present invention.

[0540] In some embodiments, anti-sealanin 18.2 antibody or its antigen binding fragment or its pharmaceutical composition is co-administered with at least one additional therapeutic agent such as, but not limited to, any therapeutic agent for treating a tumor stomach tumor (such as a DNA damaging agent). For example, in some embodiments, anti-sealanin 18.2 antibody or its antigen binding fragment or its pharmaceutical composition is co-administered with at least one additional therapeutic agent such as, but not limited to, a therapeutic agent for treating cancer or a condition associated with cancer. Examples of such treatments and therapies include, but are not limited to, Abemaciclib, Abiraterone Acetate, Abraxane (Albumin-Stable Nanoparticle Formulation of Paclitaxel), ABVD, ABVE, ABVE-PC, AC, Acalabrutinib, AC-T, Actemra (Tocilizumab), Adcetris (Brentuximab Vedotin), ADE, Ado-Trastuzumab Emtansine, Adriamycin (Doxorubicin Hydrochloride), Afatinib Dimaleate, Afinitor (Everolimus), Akynzeo (Netupitant, and Palonosetron Hydrochloride). Hydrochloride), Aldara (Imiquimod), Aldesleukin, Alecensa (Alectinib), Alectinib, Alemtuzumab, Alimta (Pemetrexed Disodium), Aliqopa (Copanlisib Hydrochloride), Alkeran (Melphalan Hydrochloride), Melphalan Tablets (Melphalan), Aloxi (Palonosetron Hydrochloride),Hydrochloride), Alunbrig (Brigatinib), Ameluz (Aminolevulinic Acid Hydrochloride), Amifostine, Aminolevulinic Acid Hydrochloride, Anastrozole, Apalutamide, Aprepitant, Aranesp (Darbepoetin Alfa), Aredia (Pamidronate Disodium), Arimidex (Anarozole), Aromasin (Exemestane), Arranon (Nelarabine), Arsenic Trioxide, Arzerra (Ofatumumab), Asparaginase Erwiniachrysanthemi, Asparlas (Calaspargase-mknl Pegol-mknl), Atezolizumab, Avastin (Bevacizumab), Avelumab, Axicabtagene Ciloleucel, Axitinib, Azacitidine, Azedra (Iodo [I 131] Benzylguanidine), Bavencio (Avelumab), BEACOPP, Beleodaq (Belinostat), Belinostat, Bendamustine Hydrochloride, Bendeka (Bendamustine Hydrochloride), BEP, Besponsa (Inotuzumab) Ozogamicin), Bevacizumab, Bexarotene, Bicalutamide, BiCNU (Carmustine), Binimetinib, Bleomycin Sulfate, Blinatumomab, Blincyto (Lantumomab), Bortezomib, Bosulif (Bosutinib), Bosutinib, Braftovi (Encorafenib), BrentuximabVedotin, Brigatinib, BuMel, Busulfan, Busulfex (Busulfan), Cabazitaxel, Cablivi (Caplacizumab-yhdp), Cabometyx (Cabozantinib-S-Malate), Cabozantinib-S-Malate, CAF, Pegolcarbazinase-mknl, Calquence (Acalabrutinib), Campath (Alemtuzumab), Camptosar (Irinotecan hydrochloride),Hydrochloride), Capecitabine, Caprucizumab-yhdp, CAPOX, Carac (fluorouracil-topical), Carboplatin, Carboplatin-paclitaxel, Carfilzomib, Carmustine, Carmustine implant, Casodex (bicalutamide), CEM, Cemiprilimab-rwlc, Ceritinib, Ce rubidine (daunorubicin hydrochloride), Cervarix (recombinant HPV bivalent vaccine), Cetuximab, CEV, Chlorambucil, Chlorambucil-prednisone, CHOP, Cisplatin, Cladribine, Clofarabine, Clolar (clofarabine), CMF, Cobimetinib, Cometriq (cabozantinib-S-malate), Cephalexin hydrochloride COPDAC, Copiktra (duvelisib), COPP, COPP-ABV, Cosmegen (actinomycin D), Cotellic (cobimetinib), Crizotinib, CVP, cyclophosphamide, Cyramza (ramucirumab), cytarabine, cytarabine liposomal, Cytosar-U (cytarabine), dabrafenib fenib), Dacarbazine, Dacogen (Decitabine), Dacomitinib, Actinomycin D, Daratumumab, Darep...

Claims

1. A recombinant antibody or an antigen-binding fragment thereof, wherein the recombinant antibody or the antigen-binding fragment thereof binds to the claudin 18.2 protein, wherein: The claudin 18.2 protein is in its native conformation.

2. The antibody or antigen-binding fragment thereof according to claim 1, wherein The claudin 18.2 protein is human claudin 18.2 protein.

3. The antibody or antigen-binding fragment thereof according to claim 1, wherein The antibody or antigen-binding fragment thereof is a humanized antibody.

4. The antibody or antigen-binding fragment thereof according to claim 1, wherein The antibody or antigen-binding fragment thereof is a chicken antibody.

5. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 4, wherein The antibody or antigen-binding fragment thereof is a monoclonal antibody.

6. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 4, wherein The antibody or antigen-binding fragment thereof is a scFv antibody.

7. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 6, wherein The antibody or antigen-binding fragment comprises: a light chain variable (V L ) region, the light chain variable (V L ) region includes a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2) and a light chain CDR3 (LCDR3), wherein the LCDR1 has an amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23; the LCDR2 has an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24; and the LCDR3 has an amino acid sequence of SEQ ID NO:

19.

8. The antibody or antigen-binding fragment thereof according to claim 7, wherein The antibody or antigen-binding fragment thereof comprises V L Area, the V L The region has an amino acid sequence that is at least 85% homologous to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:

13.

9. The antibody or antigen-binding fragment thereof according to claim 7, wherein The antibody or antigen-binding fragment thereof comprises V L Area, the V L The region has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homologous to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:

13.

10. The antibody or antigen-binding fragment thereof according to claim 7, wherein The antibody or antigen-binding fragment thereof comprises V L Area, the V L The region has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:

13.

11. The antibody or antigen-binding fragment thereof according to claim 7, wherein The antibody or antigen-binding fragment thereof comprises V L Area, the V L The region has the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, or any variant thereof having 1-10 substitutions, deletions or insertions.

12. The antibody or antigen-binding fragment thereof according to claim 7, wherein The antibody or antigen-binding fragment thereof comprises V L Area, the V L The region has the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13, or any variant thereof having 1-10 conservative substitutions.

13. The antibody or antigen-binding fragment thereof according to claim 7, wherein: The antibody or antigen-binding fragment thereof comprises V L Area, the V L The region has the amino acid sequence of SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, or SEQ ID NO:

13.

14. The antibody or antigen-binding fragment thereof according to any one of claims 7 to 13, wherein The antibody or antigen-binding fragment thereof comprises V L Area, the V L The region includes LCDR1, LCDR2 and LCDR3, wherein the LCDR1 has an amino acid sequence of SEQ ID NO: 17; the LCDR2 has an amino acid sequence of SEQ ID NO: 18; and the LCDR3 has an amino acid sequence of SEQ ID NO:

19.

15. The antibody or antigen-binding fragment thereof according to any one of claims 7 to 13, wherein The antibody or antigen-binding fragment thereof comprises V L Area, the V L The region includes LCDR1, LCDR2 and LCDR3, wherein the antibody or antigen-binding fragment thereof, wherein the LCDR1 has the amino acid sequence of SEQ ID NO:23; the LCDR2 has the amino acid sequence of SEQ ID NO:24; and the LCDR3 has the amino acid sequence of SEQ ID NO:

19.

16. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 15, wherein The antibody or antigen-binding fragment comprises: a heavy chain variable (V H ) region, the heavy chain variable (V H ) region includes a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3), wherein the HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; the HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQID NO:30 or SEQID NO:

33.

17. The antibody or antigen-binding fragment thereof according to claim 16, wherein The antibody or antigen-binding fragment thereof comprises V H Area, the V H The region has an amino acid sequence that is at least 85% homologous to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, or SEQ ID NO:

12.

18. The antibody or antigen-binding fragment thereof according to claim 16, wherein The antibody or antigen-binding fragment thereof comprises V H Area, the V H The region has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homologous to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:

12.

19. The antibody or antigen-binding fragment thereof according to claim 16, wherein The antibody or antigen-binding fragment thereof comprises V H Area, the V H The region has an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:

12.

20. The antibody or antigen-binding fragment thereof according to claim 16, wherein The antibody or antigen-binding fragment thereof comprises V H Area, the V H The region has the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, or any variant thereof having 1-10 substitutions, deletions or insertions.

21. The antibody or antigen-binding fragment thereof according to claim 16, wherein The antibody or antigen-binding fragment thereof comprises V H Area, the V H The region has the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:12, or any variant thereof having 1-10 conservative substitutions.

22. The antibody or antigen-binding fragment thereof according to claim 16, wherein The antibody or antigen-binding fragment thereof comprises V H Area, the V H The region has the amino acid sequence of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10 or SEQ ID NO:

12.

23. The antibody or antigen-binding fragment thereof according to any one of claims 16 to 22, wherein The antibody or antigen-binding fragment thereof comprises V H Area, the V H The region includes HCDR1, HCDR2 and HCDR3, wherein the HCDR1 has an amino acid sequence of SEQ ID NO: 20; the HCDR2 has an amino acid sequence of SEQ ID NO: 21; and the HCDR3 has an amino acid sequence of SEQ ID NO:

22.

24. The antibody or antigen-binding fragment thereof according to any one of claims 16 to 22, wherein The antibody or antigen-binding fragment thereof comprises V H Area, the V H The region includes HCDR1, HCDR2 and HCDR3, wherein the HCDR1 has an amino acid sequence of SEQ ID NO: 25; the HCDR2 has an amino acid sequence of SEQ ID NO: 26; and the HCDR3 has an amino acid sequence of SEQ ID NO:

27.

25. The antibody or antigen-binding fragment thereof according to any one of claims 16 to 22, wherein The antibody or antigen-binding fragment thereof comprises V H Area, the V H The region includes HCDR1, HCDR2 and HCDR3, wherein the HCDR1 has an amino acid sequence of SEQ ID NO: 28; the HCDR2 has an amino acid sequence of SEQ ID NO: 29; and the HCDR3 has an amino acid sequence of SEQ ID NO:

30.

26. The antibody or antigen-binding fragment thereof according to any one of claims 16 to 22, wherein The antibody or antigen-binding fragment thereof comprises V H Area, the V H The region includes HCDR1, HCDR2 and HCDR3, wherein the HCDR1 has an amino acid sequence of SEQ ID NO: 31; the HCDR2 has an amino acid sequence of SEQ ID NO: 32; and the HCDR3 has an amino acid sequence of SEQ ID NO:

33.

27. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 26, wherein The antibody or antigen-binding fragment comprises: (i) V L Area, the V L The region comprises LCDR1, LCDR2 and LCDR3, wherein the LCDR1 has an amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23; the LCDR2 has an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24; and the LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) V H Area, the V H The region includes HCDR1, HCDR2 and HCDR3, wherein the HCDR1 has an amino acid sequence of SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28 or SEQ ID NO:31; the HCDR2 has an amino acid sequence of SEQ ID NO:21, SEQ ID NO:26, SEQ ID NO:29 or SEQ ID NO:32; and the HCDR3 has an amino acid sequence of SEQ ID NO:22, SEQ ID NO:27, SEQ ID NO:30 or SEQ ID NO:

33.

28. The antibody or antigen-binding fragment thereof according to claim 27, wherein The antibody or antigen-binding fragment comprises: (i) V L Area, the V L The region comprises LCDR1, LCDR2 and LCDR3, wherein the LCDR1 has an amino acid sequence of SEQ ID NO: 17; the LCDR2 has an amino acid sequence of SEQ ID NO: 18; and the LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) V H Area, the V H The region includes HCDR1, HCDR2 and HCDR3, wherein the HCDR1 has an amino acid sequence of SEQ ID NO: 20; the HCDR2 has an amino acid sequence of SEQ ID NO: 21; and the HCDR3 has an amino acid sequence of SEQ ID NO:

22.

29. The antibody or antigen-binding fragment thereof according to claim 28, wherein The antibody or antigen-binding fragment comprises: (i) V L Area, the V L The region has an amino acid sequence of SEQ ID NO: 5, or a variant thereof; and (ii) V H Area, the V H The region has the amino acid sequence of SEQ ID NO: 4, or a variant thereof.

30. The antibody or antigen-binding fragment thereof according to claim 27, wherein The antibody or antigen-binding fragment comprises: (i) V L Area, the V L The region comprises LCDR1, LCDR2 and LCDR3, wherein the LCDR1 has an amino acid sequence of SEQ ID NO: 23; the LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) V H Area, the V H The region includes HCDR1, HCDR2 and HCDR3, wherein the HCDR1 has the amino acid sequence of SEQ ID NO: 25; the HCDR2 has the amino acid sequence of SEQ ID NO: 26; and the HCDR3 has the amino acid sequence of SEQ ID NO:

27.

31. The antibody or antigen-binding fragment thereof according to claim 30, wherein The antibody or antigen-binding fragment comprises: (i) V L Area, the V L The region has the amino acid sequence of SEQ ID NO: 7, or a variant thereof; and (ii) V H Area, the V H The region has the amino acid sequence of SEQ ID NO: 6, or a variant thereof.

32. The antibody or antigen-binding fragment thereof according to claim 30, wherein The antibody or antigen-binding fragment comprises: (i) V L Area, the V L The region has an amino acid sequence of SEQ ID NO: 9, or a variant thereof; and (ii) V H Area, the V H The region has the amino acid sequence of SEQ ID NO: 8, or a variant thereof.

33. The antibody or antigen-binding fragment thereof according to claim 27, wherein: The antibody or antigen-binding fragment comprises: (i) V L Area, the V L The region comprises LCDR1, LCDR2 and LCDR3, wherein the LCDR1 has an amino acid sequence of SEQ ID NO: 23; the LCDR2 has an amino acid sequence of SEQ ID NO: 24; and LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) V H Area, the V H The region includes HCDR1, HCDR2 and HCDR3, wherein the HCDR1 has the amino acid sequence of SEQ ID NO:28; the HCDR2 has the amino acid sequence of SEQ ID NO:29; and the HCDR3 has the amino acid sequence of SEQ ID NO:

30.

34. The antibody or antigen-binding fragment thereof according to claim 33, wherein The antibody or antigen-binding fragment comprises: (i) V L Area, the V L The region has the amino acid sequence of SEQ ID NO: 11, or a variant thereof; and (ii) V H Area, the V H The region has the amino acid sequence of SEQ ID NO: 10, or a variant thereof.

35. The antibody or antigen-binding fragment thereof according to claim 27, wherein The antibody or antigen-binding fragment comprises: (i) V L Area, the V L The region comprises LCDR1, LCDR2 and LCDR3, wherein the LCDR1 has an amino acid sequence of SEQ ID NO: 23; the LCDR2 has an amino acid sequence of SEQ ID NO: 24; and the LCDR3 has an amino acid sequence of SEQ ID NO: 19; and (ii) V H Area, the V H The region includes HCDR1, HCDR2 and HCDR3, wherein the HCDR1 has an amino acid sequence of SEQ ID NO: 31; the HCDR2 has an amino acid sequence of SEQ ID NO: 32; and the HCDR3 has an amino acid sequence of SEQ ID NO:

33.

36. The antibody or antigen-binding fragment thereof according to claim 35, wherein The antibody or antigen-binding fragment comprises: (i) V L Area, the V L The region has an amino acid sequence of SEQ ID NO: 13, or a variant thereof; and (ii) V H Area, the V H The region has the amino acid sequence of SEQ ID NO: 12, or a variant thereof.

37. The antibody or antigen-binding fragment thereof according to any one of claims 27 to 36, wherein The antibody or antigen-binding fragment thereof comprises V not connected by a linker L Area and V H district.

38. The antibody or antigen-binding fragment thereof according to any one of claims 7 to 24, wherein The antibody or antigen-binding fragment thereof comprises V connected by a peptide linker L Area and V H district.

39. The antibody or antigen-binding fragment thereof according to claim 38, wherein The peptide linker comprises the sequence GQSSRSSGGGGSSGGGGS (SEQ ID NO: 14); (GGGGS) n (SEQ ID NO:15)(GGGGA) n (SEQ ID NO: 16) or any combination thereof, wherein each n is independently 1-5.

40. The antibody or antigen-binding fragment thereof according to claim 38, wherein The peptide linker does not include the sequence GQSSRSSGGGGSSGGGGS (SEQ ID NO: 14).

41. The antibody or antigen-binding fragment thereof according to any one of claims 1-40, additionally comprising at least one additional peptide that binds to a different target protein.

42. The antibody or antigen-binding fragment thereof according to claim 41, wherein The different target protein is CD3 or CD28.

43. The antibody or antigen-binding fragment thereof according to claim 40 or claim 41, wherein The at least one additional peptide is an antibody or an antigen-binding fragment thereof.

44. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 43, wherein The antibody or antigen-binding fragment thereof binds to residues E56, N153, Y155, M158 and G159 of the claudin 18.2 protein.

45. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 44, wherein The antibody or antigen-binding fragment thereof binds to residues V40, E56, N153, Y155, M158, G159 and G160 of the claudin 18.2 protein.

46. ​​A nucleic acid molecule encoding the antibody or antigen-binding fragment thereof of any one of the preceding claims.

47. A vector comprising the nucleic acid molecule of claim 46.

48. A cell comprising the nucleic acid molecule of claim 46 or the vector of claim 47.

49. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of any one of claims 1-45; the nucleic acid molecule of claim 46; or the vector of claim 47.

50. The pharmaceutical composition according to claim 49, wherein The pharmaceutical composition is an injectable pharmaceutical composition.

51. The pharmaceutical composition according to claim 49 or claim 50, wherein The pharmaceutical composition is sterile and pyrogen-free.

52. A pharmaceutical composition according to any one of claims 49 to 51, wherein The pharmaceutical composition does not contain antibodies or antigen-binding fragments thereof that do not bind to claudin 18.

2.

53. A method of treating a tumor or gastric tumor in a subject, the method comprising administering the claudin 18.2 antibody or antigen-binding fragment thereof of any one of claims 1-45, or the pharmaceutical composition of any one of claims 49-52.

54. The method of claim 53, wherein: The tumor or gastric tumor is gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, or pancreatic adenocarcinoma, or non-small cell lung cancer.

55. A method according to claim 53 or claim 54, wherein: The subject is a human, mouse, sheep, rat, rabbit, shark, llama or chicken.

56. A method for detecting the presence or absence of claudin 18.2 in a sample, the method comprising contacting the sample with an antibody or antigen-binding fragment thereof according to any one of claims 1 to 45, and detecting the binding of the antibody or antigen-binding fragment thereof to the claudin 18.2 antigen, wherein: Detection of binding indicates the presence of claudin 18.2; or failure to detect binding to claudin 18.2 indicates the absence of claudin 18.

2.

57. A method of inducing an immune response against claudin 18.2 protein in a subject, the method comprising administering to the subject a virus-like particle comprising the claudin 18.2 protein under conditions sufficient to induce an immune response.

58. The method of claim 57, wherein: The subject is a human, mouse, sheep, rat, rabbit, shark, llama or chicken.

59. A method for generating antibodies or antigen-binding fragments thereof that bind to the sealing protein 18.2 protein, the method comprising administering virus-like particles comprising the sealing protein 18.2 protein on the surface thereof to a subject under conditions that induce an immune response against the sealing protein 18.2 protein to generate antibodies or antigen-binding fragments thereof that bind to the sealing protein 18.2 protein.

60. The method of claim 59, wherein: The subject is a human, mouse, sheep, rat, rabbit, shark, llama or chicken.

61. The method of claim 59 or claim 60, further comprising isolating the antibody that binds to the claudin 18.2 protein.

62. The method according to any one of claims 59 to 61, wherein: The generated antibodies or antigen-binding fragments thereof bind to the extracellular domain of the claudin 18.2 protein.

63. The method according to any one of claims 59-62, further comprising generating virus-like particles comprising the claudin 18.2 protein, the method comprising transfecting or transducing cells with the claudin 18.2 protein and a retroviral gag protein under conditions sufficient to produce the virus-like particles comprising the claudin 18.2 protein.

64. The method of claim 63, wherein: The cells are HEK-293T cells.

65. The method of claim 63 or claim 64, wherein: The gag protein is the MLV gag protein.

66. The method according to any one of claims 63 to 65, wherein: The retroviral gag protein is murine leukemia virus (MLV), gag, HIV gag or RSV gag protein.

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